Spinal cord ischemia-reperfusion injury, a severe form of spinal cord damage, can lead to sensory and motor dysfunction. This injury often occurs after traumatic events, spinal cord surgeries, or thoracoabdominal aortic surgeries. The unpredictable nature of this condition, combined with limited treatment options, poses a significant burden on patients, their families, and society. Spinal cord ischemia-reperfusion injury leads to reduced neuronal regenerative capacity and complex pathological processes. In contrast, mitophagy is crucial for degrading damaged mitochondria, thereby supporting neuronal metabolism and energy supply. However, while moderate mitophagy can be beneficial in the context of spinal cord ischemia-reperfusion injury, excessive mitophagy may be detrimental. Therefore, this review aims to investigate the potential mechanisms and regulators of mitophagy involved in the pathological processes of spinal cord ischemia-reperfusion injury. The goal is to provide a comprehensive understanding of recent advancements in mitophagy related to spinal cord ischemia-reperfusion injury and clarify its potential clinical applications.

Periodontitis is a common chronic inflammatory disease primarily caused by pathogenic microorganisms in the oral cavity. Without appropriate treatments, it may lead to the gradual destruction of the supporting tissues of the teeth. While current treatments can alleviate symptoms, they still have limitations, particularly in eliminating pathogenic bacteria, promoting periodontal tissue regeneration, and avoiding antibiotic resistance. In recent years, functional nanomaterials have shown great potential in the treatment of periodontitis due to their unique physicochemical and biological properties. This review summarizes various functionalization strategies of nanomaterials and explores their potential applications in periodontitis treatment, including metal-based nanoparticles, carbon nanomaterials, polymeric nanoparticles, and exosomes. The mechanisms and advances in antibacterial effects, immune regulation, reactive oxygen species (ROS) scavenging, and bone tissue regeneration are discussed in detail. In addition, the challenges and future directions of applying nanomaterials in periodontitis therapy are also discussed.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive lung disorder marked by deteriorating dyspnea and declining pulmonary function. Despite its rising prevalence and incidence, therapeutic options remain limited. PTEN-induced kinase 1 (PINK1), known for its role in PINK1/Parkin-dependent mitophagy, contributes to the pathogenesis of various lung diseases. In this study, we elucidate a previously unrecognized mechanism of PINK1, beyond its canonical mitophagy function, during pulmonary fibrosis. We established a bleomycin (BLM)-induced pulmonary fibrosis model in Pink1 knockout (Pink1-/-) mice and treated BEAS-2B cells with transforming growth factor-beta 1 (TGF-β1) to simulate the microenvironment of pulmonary fibrosis. A significant elevation in PINK1 expression was observed in vivo and in vitro systems. While PINK1/Parkin-dependent mitophagy was activated, mitophagy mediated by BCL2-interacting protein 3 (BNIP3) and FUN14 domain-containing 1 (FUNDC1) was suppressed. Further experiments in carbonyl cyanide m-chlorophenyl hydrazone (CCCP)-treated PINK1 knockout (KO) HEK293 cells and YFP-Parkin-expressing HeLa cells demonstrated that PINK1 deficiency enhanced BNIP3- and FUNDC1-mediated mitophagy, whereas PINK1 overexpression inhibited it. Moreover, dual BNIP3/FUNDC1 knockdown significantly reversed the anti-apoptotic effect of PINK1 KO. We conclude that PINK1 deficiency promotes the clearance of damaged mitochondria via BNIP3/FUNDC1 upregulation, preserving mitochondrial homeostasis, mitigating alveolar epithelial injury, and attenuating fibrosis. Thus, PINK1 may inhibit BNIP3- and FUNDC1-mediated mitophagy besides driving PINK1-dependent mitophagy during pulmonary fibrosis.

Copper (Cu) is an important metal pollutant commonly found in aquatic environment. Cu-based nanoparticles (NPs) have been increasingly fabricated, and led to cytotoxicity in aquatic animals. Herein, the mechanisms underlying the CuSO4/Cu-NPs-mediated perturbation of the hepatopancreatic mitochondrial function at different concentrations were investigated and compared. After exposing Eriocheir sinensis to 0 (control), 5, 50, and 500 μg/L CuSO4 and 10 μg/L Cu-NPs for 21 days, hepatopancreases were retrieved. The results revealed that Cu-NPs or excess CuSO4 induced ultrastructural damage following a time-dose effect, as indicated by swelling and degeneration of the lumen of hepatic tubules. Cu-NPs or excess CuSO4 exposure decreased the antioxidative capacity and led to the over-accumulation of reactive oxygen species (ROS). Moreover, the mitochondrial membrane potential (MMP) was reduced and apoptosis induced. Additionally, both CuSO4 and Cu-NPs increased the numbers of mitophagosomes and the mRNA and protein levels of microtubule associated protein 1 light chain 3 beta (LC3B), and triggered mitophagy through BCL2 interacting protein 3 like (BNIP3L)/Beclin1 pathway. Altogether, this study provides a basis for exploring Cu-mediated potential mitochondrial autophagy activation mechanisms, uncovered the difference between CuSO4 and Cu-NPs.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline, behavioral impairments, and psychiatric comorbidities. The pathogenesis of AD remains incompletely elucidated, despite advances in dominant hypotheses such as the β-amyloid (Aβ) cascade, tauopathy, cholinergic deficiency, and neuroinflammation mechanisms. However, these hypotheses inadequately explain the multifactorial nature of AD, which exposes limitations in our understanding of its mechanisms. Mitochondrial dysfunction is known to play a pivotal role in AD, and since patients exhibit intracellular mitochondrial dysfunction and structural changes in the brain at an early stage, correcting the imbalance of mitochondrial homeostasis and the cytopathological changes caused by it may be a potential target for early treatment of AD. Mitochondrial structural abnormalities accelerate AD pathogenesis. For instance, structural and functional alterations in the mitochondria-associated endoplasmic reticulum membrane (MAM) can disrupt intracellular Ca2⁺ homeostasis and cholesterol metabolism, consequently promoting Aβ accumulation. In addition, the overaccumulation of Aβ and hyperphosphorylated tau proteins can further damage neurons by disrupting mitochondrial integrity and mitophagy, thereby amplifying pathological aggregation and exacerbating neurodegeneration in AD. Furthermore, Aβ deposition and abnormal tau proteins can disrupt mitochondrial dynamics through dysregulation of fission/fusion proteins, leading to excessive mitochondrial fragmentation and subsequent dysfunction. Additionally, hyperphosphorylated tau proteins can impair mitochondrial transport, resulting in axonal dysfunction in AD. This article reviews the biological significance of mitochondrial structural morphology, dynamics, and mitochondrial DNA (mtDNA) instability in AD pathology, emphasizing mitophagy abnormalities as a critical contributor to AD progression. Additionally, mitochondrial biogenesis and proteostasis are critical for maintaining mitochondrial function and integrity. Impairments in these processes have been implicated in the progression of AD, further highlighting the multifaceted role of mitochondrial dysfunction in neurodegeneration. It further discusses the therapeutic potential of mitochondria-targeted strategies for AD drug development.

Mitochondria are very dynamic organelles that maintain cellular homeostasis, crucial in the central nervous system. Mitochondrial abnormalities have been described in neuropsychiatric diseases, namely major depression disorder (MDD) and schizophrenia. Since stress is the predominant non-genetic cause of MDD, and has a direct impact on mitochondrial networks, understanding how psychological stress affects mitochondrial health is vital to improve the current pharmacological therapies.

The effect of 21 days of unpredictable stress was evaluated in frontal cortex of Wistar male rats comparing protein and gene markers of mitophagy (PINK1, PARKIN, BNIP3, NIX, FUNDC1), mitochondrial biosynthesis (PGC1α, NRF1, TFAM) and dynamics (MFN1, MFN2, OPA1, DRP1), and mitochondrial presence within microglia with the MitoTracker Green FM™ probe.

Chronic mild stress (CMS) caused the upregulation of mitochondrial mass, mitochondria depolarization, dysregulation in mitochondrial dynamics towards fusion, the increase of mitophagy markers and the induction of genes that activate mitochondrial biogenesis in frontal cortex. CMS also promoted microglia recruitment and mitochondrial number boosting within them.

There is a dysregulation of mitochondrial dynamics towards fusion, an upregulation of mitophagy markers, and the induction of genes associated with mitochondrial biogenesis in response to CMS in the frontal cortex of adult rats. This study highlights the impact of psychological stress on brain mitochondrial networks.

Mitochondrial quality control plays a critical role in cytogenetic development by regulating various cell-death pathways and modulating the release of reactive oxygen species (ROS). Dysregulated mitochondrial quality control can lead to a broad spectrum of diseases, including reproductive disorders, particularly female infertility. Ovarian insufficiency is a significant contributor to female infertility, given its high prevalence, complex pathogenesis, and profound impact on women's health. Understanding the pathogenesis of ovarian insufficiency and devising treatment strategies based on this understanding are crucial. Oocytes and granulosa cells (GCs) are the primary ovarian cell types, with GCs regulated by oocytes, fulfilling their specific energy requirements prior to ovulation. Dysregulation of mitochondrial quality control through gene knockout or external stimuli can precipitate apoptosis, inflammatory responses, or ferroptosis in both oocytes and GCs, exacerbating ovarian insufficiency. This review aimed to delineate the regulatory mechanisms of mitochondrial quality control in GCs and oocytes during ovarian development. This study highlights the adverse consequences of dysregulated mitochondrial quality control on GCs and oocyte development and proposes therapeutic interventions for ovarian insufficiency based on mitochondrial quality control. These insights provide a foundation for future clinical approaches for treating ovarian insufficiency.

Alzheimer's disease (AD) is a neurological disorder that affects cognition and behavior, accounting for 60-70 % of dementia cases. Its mechanisms involve amyloid aggregates, hyperphosphorylated tau tangles, and loss of neural connections. Current treatments have limited efficacy due to a lack of specific targets. Recently, microRNAs (miRNAs) have emerged as key modulators in AD, regulating gene expression through interactions with mRNA. Dysregulation of specific miRNAs contributes to disease progression by disrupting clearance pathways. Antisense oligonucleotide (ASO)-based therapies show promise for AD treatment, particularly when combined with miRNA mimics or antagonists, targeting complex regulatory networks. However, miRNAs can interact with each other, complicating cellular processes and potentially leading to side effects. Our review emphasizes the role of miRNAs in regulating amyloid-beta (Aβ) clearance and highlights their potential as therapeutic targets and early biomarkers for AD, underscoring the need for further research to enhance their efficacy and safety.

Influenza A virus (IAV) infection causes considerable morbidity and mortality worldwide, and the secondary bacterial infection further exacerbates the severity and fatality of the initial viral infection. Mitophagy plays an important role in host resistance to pathogen infection and immune response, while its role on pulmonary epithelial cells with viral and bacterial co-infection remains unclear. The present study reveals that the secondary Staphylococcus aureus infection significantly increased the viral and bacterial loads in human lung epithelial cells (A549) during the initial H1N1 infection. Meanwhile, the secondary S. aureus infection triggered more intense mitophagy in A549 cells by activating the PINK1/Parkin signaling pathway. Notably, mitophagy could contribute to the proliferation of pathogens in A549 cells via the inhibition of cell apoptosis. Furthermore, based on an influenza A viral and secondary bacterial infected mouse model, we showed that activation of mitophagy was conducive to the proliferation of virus and bacteria in the lungs, aggravated the inflammatory damage and severe pneumonia at the same time, and eventually decreased the survival rate. The results elucidated the effect and the related molecular mechanism of mitophagy in pulmonary epithelial cells following IAV and secondary S. aureus infection for the first time, which will provide valuable information for the pathogenesis of virus/bacteria interaction and new ideas for the treatment of severe pneumonia.

Intervertebral disc degeneration (IVDD) is a prevalent condition contributing to various spinal disorders, posing a significant global health burden. Mitophagy plays a crucial role in maintaining mitochondrial quantity and quality and is closely associated with the onset and progression of IVDD. Well-documented region-specific mitophagy mechanisms in IVDD are guiding the development of therapeutic strategies. In the nucleus pulposus (NP), impaired mitochondria lead to apoptosis, oxidative stress, senescence, extracellular matrix degradation and synthesis, excessive autophagy, inflammation, mitochondrial instability, and pyroptosis, with key regulatory targets including AMPK, PGC-1α, SIRT1, SIRT3, Progerin, p65, Mfn2, FOXO3, NDUFA4L2, SLC39A7, ITGα5/β1, Nrf2, and NLRP3 inflammasome. In the annulus fibrosus (AF), mitochondrial damage induces apoptosis and oxidative stress mediated by PGC-1α, while in the cartilage endplate (CEP), mitochondrial dysfunction similarly triggers apoptosis and oxidative stress. These mechanistic insights highlight therapeutic strategies such as activating Parkin-dependent and Ub-independent mitophagy pathways for NP, enhancing Parkin-dependent mitophagy for AF, and targeting Parkin-mediated mitophagy for CEP. These strategies include the use of natural ingredients, hormonal modulation, gene editing technologies, targeted compounds, and manipulation of related proteins. This review summarizes the mechanisms of mitophagy in different regions of the intervertebral disc and highlights therapeutic approaches using mitophagy modulators to ameliorate IVDD. It discusses the complex mechanisms of mitophagy and underscores its potential as a therapeutic target. The objective is to provide valuable insights and a scientific basis for the development of mitochondrial-targeted drugs for anti-IVDD.

Alleviating the multiple types of programmed neuronal death caused by mechanical injury has been an impetus for designing neuro-therapeutical approaches after traumatic brain injury (TBI). The aim of this study was to elucidate the potential role of PSMD14 (proteasome 26S subunit, non-ATPase 14) in neuron death and the specific mechanism through which it improves prognosis of TBI patients. Here, we identified differential expression of the PSMD14 protein between the controlled cortical impact (CCI) and sham mouse groups by LC-MS proteomic analysis and found that PSMD14 was significantly upregulated in neurons after brain injury by qPCR and western blot. PSMD14 suppressed stretch-induced neuron PANoptosis and improved motor ability and learning performance after CCI in vivo. Mechanistically, PSMD14 improved PINK1 phosphorylation levels at Thr257 and activated PINK1-mediated mitophagy by deubiquitinating PKM/PKM2 (pyruvate kinase M1/2) to maintain PKM protein stability. PSMD14-induced mitophagy promoted mitochondrial homeostasis to reduced ROS production, and ultimately inhibited the neuron PANoptosis. The upregulation of neuronal PSMD14 after TBI was due to the increase of histone lactation modification level and lactate treatment alleviated neuron PANoptosis via increasing PSMD14 expression. Our findings suggest that PSMD14 could be a potential therapeutic approach for improving the prognosis of TBI patients.Abbreviations: CCI: controlled cortical impact; CQ: chloroquine; DUBs: deubiquitinating enzymes; H3K18la: H3 lysine 18 lactylation; IB: immunoblot; IHC: immunohistochemistry; IP: immunoprecipitation; MLKL: mixed lineage kinase domain like pseudokinase; PI3K: phosphoinositide 3-kinase; PINK1: PTEN induced kinase 1; PKM/PKM2: pyruvate kinase M1/2; PSMD14: proteasome 26S subunit, non-ATPase 14; ROS: reactive oxygen species; RIPK1: receptor interacting serine/threonine kinase 1; RIPK3: receptor interacting serine/threonine kinase 3; TBI: traumatic brain injury.

Neurodegenerative diseases (NDDs), such as Parkinson's disease (PD) and Alzheimer's disease (AD), are devastating brain diseases and are incurable at the moment. Increasing evidence indicates that NDDs are associated with mitochondrial dysfunction. Mitophagy removes defective or redundant mitochondria to maintain cell homeostasis, whereas deficient mitophagy accelerates the accumulation of damaged mitochondria to mediate the pathologies of NDDs. Therefore, targeting mitophagy has become a valuable therapeutic pathway for the treatment of NDDs. Several mitophagy modulators have been shown to ameliorate neurodegeneration in PD and AD. However, it remains to be further investigated for other NDDs. Here, we describe the mechanism and key signaling pathway of mitophagy and summarize the roles of defective mitophagy on the pathogenesis of NDDs. Further, we underline the development advances of mitophagy modulators for PD and AD therapy, discuss the therapeutic challenges and limitations of the existing modulators, and provide guidelines for mitophagy mechanism exploration and drug design.

Dysfunctional mitochondria are present in many neurodegenerative diseases, such as spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph disease (MJD). SCA3/MJD, the most frequent neurodegenerative ataxia worldwide, is caused by the abnormal expansion of the polyglutamine tract (polyQ) at ataxin-3. This protein is known to deubiquitinate key proteins such as Parkin, which is required for mitophagy. Ataxin-3 also interacts with Beclin1 (essential for initiating autophagosome formation adjacent to mitochondria), as well as with the mitochondrial cristae protein TBK1. To identify other proteins of the mitophagy pathway (according to the KEGG database) that can interact with ataxin-3, here we developed a pipeline for in silico analyses of protein-protein interactions (PPIs), called auto-p2docking. Containerized in Docker, auto-p2docking ensures reproducibility and reduces the number of errors through its simplified configuration. Its architecture consists of 22 modules, here used to develop 12 protocols but that can be specified according to user needs. In this work, we identify 45 mitophagy proteins as putative ataxin-3 interactors (53% are novel), using ataxin-3 interacting regions for validation. Furthermore, we predict that ataxin-3 interactors from both Parkin-independent and -dependent mechanisms are affected by the polyQ expansion.

Calcium signaling plays a pivotal role in diverse cellular processes through precise spatiotemporal regulation and interaction with effector proteins across distinct subcellular compartments. Mitochondria, in particular, act as central hubs for calcium buffering, orchestrating energy production, redox balance and apoptotic signaling, among others. While controlled mitochondrial calcium uptake supports ATP synthesis and metabolic regulation, excessive accumulation can trigger oxidative stress, mitochondrial membrane permeabilization, and cell death. Emerging findings underscore the intricate interplay between calcium homeostasis and mitophagy, a selective type of autophagy for mitochondria elimination. Although the literature is still emerging, this review delves into the bidirectional relationship between calcium signaling and mitophagy pathways, providing compelling mechanistic insights. Furthermore, we discuss how disruptions in calcium homeostasis impair mitophagy, contributing to mitochondrial dysfunction and the pathogenesis of common neurodegenerative diseases.

Ischemic stroke (IS) is a prevalent neurological disorder often resulting in significant disability or mortality. Resveratrol, extracted from Polygonum cuspidatum Sieb. et Zucc. (commonly known as Japanese knotweed), has been recognized for its potent neuroprotective properties. However, the neuroprotective efficacy of its derivative, (E)-4-(3,5-dimethoxystyryl) quinoline (RV02), against ischemic stroke remains inadequately explored. This study aimed to evaluate the protective effects of RV02 on neuronal ischemia-reperfusion injury both in vitro and in vivo. The research utilized an animal model of middle cerebral artery occlusion/reperfusion and SH-SY5Y cells subjected to oxygen-glucose deprivation and reperfusion to simulate ischemic conditions. The findings demonstrate that RV02 attenuates neuronal mitochondrial damage and scavenges reactive oxygen species (ROS) through mitophagy activation. Furthermore, Parkin knockdown was found to abolish RV02's ability to activate mitophagy and neuroprotection in vitro. These results suggest that RV02 shows promise as a neuroprotective agent, with the activation of Parkin-mediated mitophagy potentially serving as the primary mechanism underlying its neuroprotective effects.

Chronic inflammation is a cancer hallmark and chronic exposure to interleukin-1 (IL-1) transforms castration-sensitive prostate cancer (PCa) cells into more fit castration-insensitive PCa cells. p62 is a scaffold protein that protects cells from nutrient deprivation via autophagy and from cytotoxic reactive oxygen via NFκB and NRF2 antioxidant signaling. Herein, we report that the LNCaP PCa cell line acquires high basal accumulation of the p62-KEAP1 complex when chronically exposed to IL-1. p62 promotes non-canonical NRF2 antioxidant signaling by binding and sequestering KEAP1 to the autophagosome for degradation. But despite high basal p62-KEAP1 accumulation, only two of several NRF2-induced genes analyzed, GCLC and HMOX1, showed high basal mRNA levels, suggesting that the high basal p62-KEAP1 accumulation does not result in overall high basal NRF2 activity. Nutrient starvation induces NRF2-dependent GCLC upregulation and HMOX1 repression, and we found that chronic IL-1-exposed LNCaP cells show hypersensitivity to serum starvation-induced GCLC and HMOX1 regulation. Thus, chronic IL-1 exposure affects cell response to nutrient stress. While HMOX1 expression remains NRF2/KEAP1-dependent in chronic IL-1-exposed LNCaP cells, GCLC expression is NRF2/KEAP1-independent. Furthermore, the high basal p62-KEAP1 complex accumulation is not required to regulate GCLC or HMOX1 expression, suggesting cells chronically exposed to IL-1 evolve a novel NRF2-independent role for the p62/KEAP1 axis.

Sarcopenia is a geriatric condition characterized by a decrease in skeletal muscle mass and function, significantly impacting both quality of life and overall health. Mitochondria are the main sites of energy production within the cell, and also produce reactive oxygen species (ROS), which maintain mitochondrial homeostasis-mitophagy (clearing damaged mitochondria); mitochondrial dynamics, which involve fusion and fission to regulate mitochondrial morphology; mitochondrial biogenesis, which ensures the functionality and homeostasis of mitochondria. Sarcopenia is linked to mitochondrial dysfunction, suggesting that muscle mitochondrial function therapy should be investigated. Extrinsic therapies are extensively examined to identify new treatments for muscular illnesses including sarcopenia. Changes in muscle physiology and lifestyle interventions, such as pharmacological treatments and exercise, can modulate mitochondrial activity in older adults. This PubMed review encompasses the most significant mitophagy and sarcopenia research from the past five years. Animal models, cellular models, and human samples are well covered. The review will inform the development of novel mitochondria-targeted therapies aimed at combating age-related muscle atrophy.

Emergency intravascular interventional therapy is the most effective approach to rapidly restore blood flow and manage occlusion of major blood vessels during the initial phase of acute ischemic stroke. Nevertheless, several patients continue to experience ineffective reperfusion or cerebral no-reflow phenomenon, that is, hypoperfusion of cerebral blood supply after treatment. This is primarily attributed to downstream microcirculation disturbance. As integral components of the cerebral microvascular structure, endothelial cells (ECs) attach importance to regulating microcirculatory blood flow. Unlike neurons and microglia, ECs harbor a relatively low abundance of mitochondria, acting as key sensors of environmental and cellular stress in regulating the viability, structural integrity, and function of ECs rather than generating energy. Mitochondria dysfunction including increased mitochondrial reactive oxygen species levels and disturbed mitochondrial dynamics causes endothelial injury, further causing microcirculation disturbance involved in the cerebral no-reflow phenomenon. Therefore, this review aims to discuss the role of mitochondrial changes in regulating the role of ECs and cerebral microcirculation blood flow during I/R injury. The outcomes of the review will provide promising potential therapeutic targets for future prevention and effective improvement of the cerebral no-reflow phenomenon.

Prolonged exposure to environments with high concentrations of crystalline silica (CS) can lead to silicosis. Macrophages play a crucial role in the pathogenesis of silicosis. In the process of silicosis, silica (SiO2) invades alveolar macrophages (AMs) and induces mitophagy which usually exists in three states: normal, excessive, and/or deficiency. Different mitophagy states lead to corresponding toxic responses, including successful macrophage repair, injury, necrosis, apoptosis, and even pulmonary fibrosis. This is a complex process accompanied by various cytokines. Unfortunately, the details have not been fully systematically summarized. Therefore, it is necessary to elucidate the role of macrophage mitophagy in SiO2-induced pulmonary fibrosis by systematic analysis on the literature reports. In this review, we first summarized the current data on the macrophage mitophagy in the development of SiO2-induced pulmonary fibrosis. Then, we introduce the molecular mechanism on how SiO2-induced mitophagy causes pulmonary fibrosis. Finally, we focus on introducing new therapies based on newly developed mitophagy-inducing strategies. We conclude that macrophage mitophagy plays a multifaceted role in the progression of SiO2-induced pulmonary fibrosis, and reprogramming the macrophage mitophagy state accordingly may be a potential means of preventing and treating pulmonary fibrosis.

Many types of RNA viruses, including the hepatitis C virus (HCV), activate autophagy in infected cells to promote viral growth and counteract the host defense response. Autophagy acts as a catabolic pathway in which unnecessary materials are removed via the lysosome, thus maintaining cellular homeostasis. The HCV non-structural 5A (NS5A) protein is a phosphoprotein required for viral RNA replication, virion assembly, and the determination of interferon (IFN) sensitivity. Recently, increasing evidence has shown that HCV NS5A can induce autophagy to promote mitochondrial turnover and the degradation of hepatocyte nuclear factor 1 alpha (HNF-1α) and diacylglycerol acyltransferase 1 (DGAT1). In this review, we summarize recent progress in understanding the detailed mechanism by which HCV NS5A triggers autophagy, and outline the physiological significance of the balance between host-virus interactions.

Macroautophagy/autophagy is primarily accountable for the degradation of damaged organelles and toxic macromolecules in the cells. Regarding the essential function of autophagy for preserving cellular homeostasis, changes in, or dysfunction of, autophagy flux can lead to disease development. In the current paper, the complicated function of autophagy in aging-associated pathologies and cancer is evaluated, highlighting the underlying molecular mechanisms that can affect longevity and disease pathogenesis. As a natural biological process, a reduction in autophagy is observed with aging, resulting in an accumulation of cell damage and the development of different diseases, including neurological disorders, cardiovascular diseases, and cancer. The MTOR, AMPK, and ATG proteins demonstrate changes during aging, and they are promising therapeutic targets. Insulin/IGF1, TOR, PKA, AKT/PKB, caloric restriction and mitochondrial respiration are vital for lifespan regulation and can modulate or have an interaction with autophagy. The specific types of autophagy, such as mitophagy that degrades mitochondria, can regulate aging by affecting these organelles and eliminating those mitochondria with genomic mutations. Autophagy and its specific types contribute to the regulation of carcinogenesis and they are able to dually enhance or decrease cancer progression. Cancer hallmarks, including proliferation, metastasis, therapy resistance and immune reactions, are tightly regulated by autophagy, supporting the conclusion that autophagy is a promising target in cancer therapy.

Tri(1,3-dichloro-2-propyl)phosphate (TDCPP) is one of the most widely used organophosphorus flame retardants in consumer products. TDCPP has been confirmed to be neurotoxic, but its mechanism has not been clarified and may be related to mitophagy. AMBRA1 can promote neurological autophagy, but whether AMBRA1 is involved in the mechanism of TDCPP-induced neurotoxicity has not been elucidated. In this study, the optimal neuronal damage model was established by exposing mice hippocampal neurons to TDCPP. Furthermore, on the basis of this model, siRNA was used to knock down AMBRA1. Combined with qRT-PCR and Western blot techniques, we identified AMBRA1-mediated mitophagy-induced neuronal damage in vitro mechanism. The experimental results indicated that TDCPP treatment for 24 h led to a decrease in the cell viability of mouse hippocampal neurons, causing neuronal damage. Meanwhile, TDCPP exposure increased autophagy marker proteins p62 and LC3B, and down-regulated mitochondrial DNA ND1 damage and TOMM20 protein, suggesting that TDCPP exposure promoted mitophagy. In addition, TDCPP exposure led to changes in the expression of AMBRA1 and the key factors of mitophagy, FUNDC1, PINK1, and PARKIN, whereas mitophagy was inhibited after knockdown of AMBRA1. The research results indicated that exposure to TDCPP induced neuronal damage and promoted mitophagy. The mechanism may be that AMBRA1 promoted mitophagy in neuronal cells through the PARKIN-dependent/non-dependent pathway. This study revealed the toxic effects of TDCPP on the nervous system and its potential molecular mechanisms, which provided important clues for further understanding the mechanism of action of AMBAR1-mediated mitophagy.

Genetic studies of blood pressure (BP) traits to date have been performed on conventional measures by brachial cuff sphygmomanometer for systolic BP (SBP) and diastolic BP, integrating several physiologic occurrences. Genetic associations with central SBP (cSBP) have not been well-studied. Genetic discovery studies of BP have been most often performed in European-ancestry samples. Here, we investigated genetic associations with cSBP in a Chinese population and functionally validated the impact of a novel associated coiled-coil domain containing 93 (CCDC93) gene on BP regulation. An exome-wide association study (EWAS) was performed using a mixed linear model of non-invasive cSBP and peripheral BP traits in a Han Chinese population (N = 5,954) from Beijing, China genotyped with a customized Illumina ExomeChip array. We identified four SNP-trait associations with three SNPs, including two novel associations (rs2165468-SBP and rs33975708-cSBP). rs33975708 is a coding variant in the CCDC93 gene, c.535C>T, p.Arg179Cys (MAF = 0.15%), and was associated with increased cSBP (β = 29.3 mmHg, P = 1.23x10-7). CRISPR/Cas9 genome editing was used to model the effect of Ccdc93 loss in mice. Homozygous Ccdc93 deletion was lethal prior to day 10.5 of embryonic development. Ccdc93+/- heterozygous mice were viable and morphologically normal, with 1.3-fold lower aortic Ccdc93 protein expression (P = 0.0041) and elevated SBP as compared to littermate Ccdc93+/+ controls (110±8 mmHg vs 125±10 mmHg, P = 0.016). Wire myography of Ccdc93+/- aortae showed impaired acetylcholine-induced relaxation and enhanced phenylephrine-induced contraction. RNA-Seq transcriptome analysis of Ccdc93+/- mouse thoracic aortae identified significantly enriched pathways altered in fatty acid metabolism and mitochondrial metabolism. Plasma free fatty acid levels were elevated in Ccdc93+/- mice (96±7mM vs 124±13mM, P = 0.0031) and aortic mitochondrial dysfunction was observed through aberrant Parkin and Nix protein expression. Together, our genetic and functional studies support a novel role of CCDC93 in the regulation of BP through its effects on vascular mitochondrial function and endothelial function.

Cancer stem cells represent a resilient subset within the tumor microenvironment capable of differentiation, regeneration, and resistance to chemotherapeutic agents, often using dormancy as a shield. Their unique properties, including drug resistance and metastatic potential, pose challenges for effective targeting. These cells exploit certain metabolic processes for their maintenance and survival. One of these processes is autophagy, which generally helps in energy homeostasis but when hijacked by CSCs can help maintain their stemness. Thus, it is often referred as an Achilles heel in CSCs, as certain cancers tend to depend on autophagy for survival. Autophagy, while crucial for maintaining stemness in cancer stem cells (CSCs), can also serve as a vulnerability in certain contexts, making it a complex target for therapy. Regulators of autophagy like AMPK (5' adenosine monophosphate-activated protein kinase) also play a crucial role in maintaining CSCs stemness by helping CSCs in metabolic reprogramming in harsh environments. The purpose of this review is to elucidate the interplay between autophagy and AMPK in CSCs, highlighting the challenges in targeting autophagy and discussing therapeutic strategies to overcome these limitations. This review focuses on previous research on autophagy and its regulators in cancer biology, particularly in CSCs, addresses the remaining unanswered questions, and potential targets for therapy are also brought to attention.

Skin aging is the result of two types of aging, "intrinsic aging" an inevitable consequence of physiologic and genetically determined changes and "extrinsic aging," which is dependent on external factors such as exposure to sunlight, smoking, and dietary habits. UVB causes skin injury through the generation of free radicals and other oxidative byproducts, also contributing to DNA damage. Appearance and accumulation of senescent cells in the skin are considered one of the hallmarks of aging in this tissue. Mitochondria play an important role for the development of cellular senescence, in particular stress-induced senescence of human cells. However, many aspects of mitochondrial physiology relevant to cellular senescence and extrinsic skin aging remain to be unraveled. Here, we demonstrate that mitochondria damaged by UVB irradiation of human dermal fibroblasts (HDF) are eliminated by NIX-dependent mitophagy and that this process is important for cell survival under these conditions. Additionally, UVB-irradiation of human dermal fibroblasts (HDF) induces the shedding of extracellular vesicles (EVs), and this process is significantly enhanced in UVB-irradiated NIX-depleted cells. Our findings establish NIX as the main mitophagy receptor in the process of UVB-induced senescence and suggest the release of EVs as an alternative mechanism of mitochondrial quality control in HDF.

Flavored e-cigarettes are a popular alternative to cigarette smoking; unfortunately, the extrapulmonary effects are not well-characterized. Human proximal tubule cells were cultured for 24 or 48 h with 0-1000 µM ethyl vanillin (ETH VAN) and cytotoxicity evaluated. Mitochondrial health was significantly diminished following 48 h of exposure, accompanied by significantly decreased spare capacity, coupling efficiency, and ATP synthase expression. ETH VAN at 24 h inhibited glycolysis. The endoplasmic reticulum (ER) stress marker C/EBP homologous protein (CHOP) was increased at 100 μM relative to 500-1000 μM. The downstream proapoptotic marker cleaved caspase-3 subsequently showed a decreasing trend in expression after 48 h of exposure. The autophagy biomarkers microtubule-associated proteins 1A/1B light chain 3 (LC3B-I and LC3B-II) were measured by Western blot. LC3B-II levels and the LC3B-II/LC3B-I ratio increased at 24 h, which suggested activation of autophagy. In contrast, by 48 h, the autophagy biomarker LC3B-II decreased, resulting in no change in the LC3B-II/LC3B-I ratio. Mitophagy biomarker PTEN-induced putative kinase 1 (PINK1) expression decreased after 48 h of exposure. The downstream marker Parkin was not significantly changed after 24 or 48 h. These findings indicate that the flavoring ETH VAN can induce energy pathway dysfunction and cellular stress responses in a renal model.

Metabolic dysfunction-associated steatotic liver disease (MASLD) affects approximately one-third of the global population. MASLD and its advanced-stage liver fibrosis and cirrhosis are the leading causes of liver failure and liver-related death worldwide. Mitochondria are crucial organelles in liver cells for energy generation and the oxidative metabolism of fatty acids and carbohydrates. Recently, mitochondrial dysfunction in liver cells has been shown to play a vital role in the pathogenesis of MASLD and liver fibrosis. Mitophagy, a selective form of autophagy, removes and recycles impaired mitochondria. Although significant advances have been made in understanding mitophagy in liver diseases, adequate summaries concerning the contribution of liver cell mitophagy to MASLD and liver fibrosis are lacking. This review will clarify the mechanism of liver cell mitophagy in the development of MASLD and liver fibrosis, including in hepatocytes, macrophages, hepatic stellate cells, and liver sinusoidal endothelial cells. In addition, therapeutic strategies or compounds related to hepatic mitophagy are also summarized. In conclusion, mitophagy-related therapeutic strategies or compounds might be translational for the clinical treatment of MASLD and liver fibrosis.

Mitochondria, essential organelles orchestrating cellular metabolism, have emerged as central players in various disease pathologies. Recent research has shed light on mitohormesis, a concept proposing an adaptive response of mitochondria to minor disturbances in homeostasis, offering novel therapeutic avenues for mitochondria-related diseases. This comprehensive review explores the concept of mitohormesis, elucidating its induction mechanisms and occurrence. Intracellular molecules like reactive oxygen species (ROS), calcium, mitochondrial unfolded proteins (UPRmt), and integrated stress response (ISR), along with external factors such as hydrogen sulfide (H2S), physical stimuli, and exercise, play pivotal roles in regulating mitohormesis. Based on the available evidence, we elucidate how mitohormesis maintains mitochondrial homeostasis through mechanisms like mitochondrial quality control and mitophagy. Furthermore, the regulatory role of mitohormesis in mitochondria-related diseases is discussed. By envisioning future applications, this review underscores the significance of mitohormesis as a potential therapeutic target, paving the way for innovative interventions in disease management.

Macroautophagy is thought to have a critical role in shaping and refining cellular proteostasis in eukaryotic cells recovering from DNA damage. Here, we report a mechanism by which autophagy is suppressed in cells exposed to bacterial toxin-, chemical-, or radiation-mediated sources of genotoxicity. Autophagy suppression is directly linked to cellular responses to DNA damage, and specifically the stabilization of the tumor suppressor p53, which is both required and sufficient for regulating the ubiquitination and proteasome-dependent reduction in cellular pools of microtubule-associated protein 1 light chain 3 (LC3A/B), a key precursor of autophagosome biogenesis and maturation, in both epithelial cells and an ex vivo organoid model. Our data indicate that suppression of autophagy, through a newly identified p53-proteasome-LC3 axis, is a conserved cellular response to multiple sources of genotoxicity. Such a mechanism could potentially be important for realigning proteostasis in cells undergoing DNA damage repair.

The use of flavored e-liquids in electronic nicotine delivery systems (ENDS) has become very popular in recent years, but effects of these products have not been well characterized outside the lung. In this study, acute exposure to the popular flavoring vanillin (VAN) was performed on human proximal tubule (HK-2) kidney cells. Cells were exposed to 0-1000 μM VAN for 24 or 48 h and cellular stress responses were determined. Mitochondrial viability using MTT assay showed a significant decrease between the control and 1000 μM group by 48 h. Seahorse XFp analysis showed significantly increased basal respiration, ATP production, and proton leak after 24 h exposure. By 48 h exposure, these parameters remained significantly increased in addition to non-mitochondrial respiration and maximal respiration. Glycolytic activity after 24 h exposure showed significant decreases in glycolysis, glycolytic capacity, glycolytic reserve, and non-glycolytic acidification. The autophagy markers microtubule-associated protein 1A/1B light chain 3 (LC3B-I and LC3B-II) were probed via western blotting. The ratio of LC3B-II/LC3B-I was significantly increased after 24 h exposure to VAN, but by 48 h this ratio significantly decreased. The mitophagy marker PINK1 showed an increasing trend at 24 h, and its downstream target Parkin was significantly increased between the control and 750 μM group only. Finally, the oxidative stress marker 4-HNE was significantly decreased after 48 h exposure to VAN. These results indicate that acute exposure to VAN in the kidney HK-2 model can induce energy and autophagic changes within the cell.

Chronic kidney disease (CKD) represents a significant global health concern, with renal fibrosis emerging as a prevalent and ultimate manifestation of this condition. The absence of targeted therapies presents an ongoing and substantial challenge. Accumulating evidence suggests that the integrity and functionality of mitochondria within renal tubular epithelial cells (RTECs) often become compromised during CKD development, playing a pivotal role in the progression of renal fibrosis. Mitophagy, a specific form of autophagy, assumes responsibility for eliminating damaged mitochondria to uphold mitochondrial equilibrium. Dysregulated mitophagy not only correlates with disrupted mitochondrial dynamics but also contributes to the advancement of renal fibrosis in CKD. While numerous studies have examined mitochondrial metabolism, ROS (reactive oxygen species) production, inflammation, and apoptosis in kidney diseases, the precise pathogenic mechanisms underlying mitophagy in CKD remain elusive. The exact mechanisms through which modulating mitophagy mitigates renal fibrosis, as well as its influence on CKD progression and prognosis, have not undergone systematic investigation. The role of mitophagy in AKI has been relatively clear, but the role of mitophagy in CKD is still rare. This article presents a comprehensive review of the current state of research on regulating mitophagy as a potential treatment for CKD. The objective is to provide fresh perspectives, viable strategies, and practical insights into CKD therapy, thereby contributing to the enhancement of human living conditions and patient well-being.

Duck plague virus (DPV) is extremely infectious and lethal, so antiviral drugs are urgently needed. Our previous study shows that DPV infection with duck embryo fibroblast (DEF) induces reactive oxygen species (ROS) changes and promotes apoptosis. In this study, we tested the antiviral effect of the carbonyl cyanide m-chlorophenyl hydrazone (CCCP), a common mitochondrial autophagy inducer. Our results demonstrated a dose-dependent anti-DPV effect of CCCP, CCCP-treatment blocked the intercellular transmission of DPV after infection, and we also proved that CCCP could have an antiviral effect up to 48 hpi. The addition of CCCP reversed the DPV-induced ROS changes, CCCP can inhibit virus-induced apoptosis; meanwhile, CCCP can affect mitochondrial fusion and activate mitophagy to inhibit DPV. In conclusion, CCCP can be an effective antiviral candidate against DPV.

Mitochondrial dysfunction is linked to degenerative diseases, resulting from cardiolipin (CL)-induced disruption of cristae structure in the inner mitochondrial membrane (IMM); therefore, preserving cristae and preventing CL remodeling offer effective strategies to maintain mitochondrial function. To identify reactive oxygen species (ROS)-blocking agents against mitochondrial dysfunction, a library of cyclohexylamine-containing cell-penetrating α-helical amphipathic "bundle" peptides were screened. Among these, CMP3013 is selectively bound to abnormal mitochondria, preserving the cristae structure impaired by mitochondria-damaging agents. With a stronger affinity for CL compared with other IMM lipid components, CMP3013 exhibited high selectivity. Consequently, it protected cristae, reduced ROS production, and enhanced adenosine triphosphate (ATP) generation. In mouse models of acute kidney injury, a 1 mg/kg dose of CMP3013 demonstrated remarkable efficacy, highlighting its potential as a therapeutic agent for mitochondrial dysfunction-related disorders. Overall, CMP3013 represents a promising agent for mitigating mitochondrial dysfunction and associated diseases.

Selective removal of dysfunctional mitochondria via autophagy is crucial for the maintenance of cellular homeostasis. This event is initiated by the translocation of the E3 ubiquitin ligase Parkin to damaged mitochondria, and it requires the Serine/Threonine-protein kinase PINK1. In a coordinated set of events, PINK1 operates upstream of Parkin in a linear pathway that leads to the phosphorylation of Parkin, Ubiquitin, and Parkin mitochondrial substrates, to promote ubiquitination of outer mitochondrial membrane proteins. Ubiquitin-decorated mitochondria are selectively recruiting autophagy receptors, which are required to terminate the organelle via autophagy. In this work, we show a previously uncharacterized molecular pathway that correlates the activation of the Ca2+-dependent phosphatase Calcineurin to Parkin translocation and Parkin-dependent mitophagy. Calcineurin downregulation or genetic inhibition prevents Parkin translocation to CCCP-treated mitochondria and impairs stress-induced mitophagy, whereas Calcineurin activation promotes Parkin mitochondrial recruitment and basal mitophagy. Calcineurin interacts with Parkin, and promotes Parkin translocation in the absence of PINK1, but requires PINK1 expression to execute mitophagy in MEF cells. Genetic activation of Calcineurin in vivo boosts basal mitophagy in neurons and corrects locomotor dysfunction and mitochondrial respiratory defects of a Drosophila model of impaired mitochondrial functions. Our study identifies Calcineurin as a novel key player in the regulation of Parkin translocation and mitophagy.

Yi Mai granule (YMG) consists of two classic Chinese medicine formulas used to treat cardiovascular disease for centuries. The Pink1-Mfn2-Parkin pathway, a well-recognized mechanism that mediates mitochondrial autophagy, plays a big part in mitochondrial quality control and the maintenance of heart function. However, the effects of YMG on endothelial dysfunction and mitochondrial autophagy remain unknown.

Here, we focused on the therapeutic effects of YMG in improving mitochondrial autophagy and the mechanism of YMG against cardiovascular disease.

In this study, rats were fed high-fat diet (HFD) for 21 weeks and were given high, medium, and low doses of YMG in stomach. The open field test was used to evaluate the rats' behavior. Atherosclerotic plaques, blood lipids, and cytokine levels were measured. Mitochondrial autophagy changes were observed by Transmission electron microscope (TEM). Human umbilical vein endothelial cells (HUVECs) were injured by angiotensinⅡ(AngⅡ) and were given high, medium, and low doses of YMG medicated serum in cell culture medium. Pink1-Mfn2-Parkin expression and miRNA 125a-5p expression were measured by RT-PCR and Western blot.

We demonstrated that the atherosclerosis model group tended to exhibit reduced vitality behaviors. We proved that the atherosclerosis model group showed obvious atherosclerotic plaques, endothelial cells destruction, and high level of blood lipid and cytokines (including hs-CRP, ET). Mitochondria were reduced, and mitophagy was inhibited in aortic cells of the model group. MiRNA-125a-5p was up-regulated; at the same time, Pink1-Mfn2-Parkin-mediated mitochondrial autophagy was prevented. We also proved that AngⅡinjured HUVEC showed obviously low mRNA levels of Pink1, Mfn2, and Parkin. Interestingly, we found that miRNA-125a-5p was significantly down regulated in Ang II-induced HUVECs. In addition, miRNA-125a-5p significantly reduced the protective effect of YiMai Granules against Ang II injury.

Our finding indicated that Pink1-Mfn2-Parkin-mediated mitochondrial autophagy plays a crucial role in alleviating atherosclerosis. YMG alleviated atherosclerosis by potentially activating mitochondrial autophagy may via miRNA-125a-5p, regulating Pink1-Mfn2-Parkin pathway, and regulating proinflammatory factors, vasoconstriction cytokine, and blood lipids.

Eukaryotic cells engage in autophagy, an internal process of self-degradation through lysosomes. Autophagy can be classified as selective or non-selective depending on the way it chooses to degrade substrates. During the process of selective autophagy, damaged and/or redundant organelles like mitochondria, peroxisomes, ribosomes, endoplasmic reticulum (ER), lysosomes, nuclei, proteasomes, and lipid droplets are selectively recycled. Specific cargo is delivered to autophagosomes by specific receptors, isolated and engulfed. Selective autophagy dysfunction is closely linked with cancers, neurodegenerative diseases, metabolic disorders, heart failure, etc. Through reviewing latest research, this review summarized molecular markers and important signaling pathways for selective autophagy, and its significant role in cancers. Moreover, we conducted a comprehensive analysis of small-molecule compounds targeting selective autophagy for their potential application in anti-tumor therapy, elucidating the underlying mechanisms involved. This review aims to supply important scientific references and development directions for the biological mechanisms and drug discovery of anti-tumor targeting selective autophagy in the future.