• lipid droplet
• mitochondria
• triglyceride
• white adipocyte

• Mitochondria/metabolism
• Mitochondria/genetics
• Animals
• Cytoplasm/metabolism
• Adipocytes, White/metabolism
• Adipocytes, White/cytology
• DNA, Mitochondrial/metabolism
• DNA, Mitochondrial/genetics
• Mice
• Oxidation-Reduction
• Diacylglycerol O-Acyltransferase/metabolism
• Diacylglycerol O-Acyltransferase/genetics
• Mitochondrial Proteins/metabolism
• Mitochondrial Proteins/genetics

• cell metabolism
• metabolic syndrome
• obesity
• organelles
• prohibitins

• circadian misalignment
• glucose regulation
• human
• metabolomics
• proteomics
• sleep

• Humans
• Leukocytes, Mononuclear/metabolism
• Insulin/metabolism
• Insulin/blood
• Circadian Rhythm
• Inflammation/metabolism
• Inflammation/blood
• Male
• Adult
• Shift Work Schedule
• Female
• Proteomics/methods
• Blood Glucose/metabolism
• Signal Transduction
• Insulin Resistance
• Young Adult

• P30 ES025128 NIEHS NIH HHS
• P41 GM103493 NIGMS NIH HHS
• R01 ES030113 NIEHS NIH HHS
• BB/I019405/1 UK Biotechnology and Biological Sciences Research Council

• adipocyte targeting anti‐obesity gene knockdown
• dissolving microneedle
• dual shRNA
• oligopeptoplexes
• self‐assembly

• Humans
• Mice
• Animals
• Diabetes Mellitus, Type 2/drug therapy
• Obesity/drug therapy
• Adipocytes
• Administration, Cutaneous
• Genetic Therapy
• Drug Delivery Systems

• NRF-RS-2023-00208982 National Research Foundation of Korea
• 2020H1D3A1A02081229 National Research Foundation of Korea
• 5199990514440 Brain Korea 21 Fostering Outstanding Universities for Research
• HN21C0885 Korea Drug Development Fund
• S3303329 Technology Development Program funded by the Ministry of SMEs and Startups

• Animals
• Humans
• Mice
• Cholesterol/metabolism
• Homeostasis
• Lipid Metabolism
• Lipids
• Prohibitins
• Repressor Proteins/genetics
• Repressor Proteins/metabolism
• RNA, Messenger/genetics
• RNA, Messenger/metabolism

• Biochemistry
• Endocrinology
• Small molecule

• RSPO1
• Wnt signaling
• obesity
• pathogenic gene
• thermogenesis
• whole-exome sequencing

• Humans
• Mice
• Animals
• Adiposity/genetics
• Adipocytes, Beige/metabolism
• Obesity/genetics
• Obesity/metabolism
• Adipose Tissue, Brown/metabolism
• Diet, High-Fat/adverse effects
• Thermogenesis/genetics
• Mutation/genetics
• Thrombospondins/genetics
• Thrombospondins/metabolism

• 2022YFC2505201 National Key Research and Development Program of China
• 2021YFA1301103 National Key Research and Development Program of China
• 91957124 National Natural Science Foundation of China
• 92157204 National Natural Science Foundation of China
• 82088102 National Natural Science Foundation of China
• 82250901 National Natural Science Foundation of China
• 82050007 National Natural Science Foundation of China
• 81930021 National Natural Science Foundation of China
• 81822009 National Natural Science Foundation of China
• 91857205 National Natural Science Foundation of China
• 81730023 National Natural Science Foundation of China
• 81870585 National Natural Science Foundation of China
• Innovative research team of high-level local universities in Shanghai
• 20161306 Shanghai Municipal Education Commission-Gaofeng Clinical Medicine
• 20171903 Shanghai Municipal Education Commission-Gaofeng Clinical Medicine
• 2018BR01 Outstanding Academic Leader Program of Shanghai Municipal Health Commission
• 21JC1404400 Science and Technology Commission of Shanghai Municipality
• 20XD1403200 Program of Shanghai Academic/Technology Research Leader
• National Key Research and Development Program of China
• National Natural Science Foundation of China
• Science and Technology Commission of Shanghai Municipality
• Program of Shanghai Academic/Technology Research Leader

• DRP1
• MFN2
• OPA1
• cAMP/PKA
• mitochondria
• mitochondrial dynamics
• ovarian cancer
• prohibitin

• Humans
• Female
• Mitochondrial Dynamics
• Mitochondria/metabolism
• Mitochondrial Membranes/metabolism
• Ovarian Neoplasms/metabolism
• Mitochondrial Proteins/metabolism
• Dynamins/metabolism

The incidence of age-related neurodegenerative disorders has risen with the increase of life expectancy. Unfortunately, the diagnosis of such disorders is in most cases only possible when the neurodegeneration status is already advanced, and symptoms are evident. Although age-related neurodegeneration is a common phenomenon in living animals, the cellular and molecular mechanisms behind remain poorly understood. Pathways leading to neurodegeneration usually diverge from a common starting point, mitochondrial stress, which can serve as a potential target for early diagnosis and treatments. Interestingly, the evolutionarily conserved mitochondrial prohibitin (PHB) complex is a key regulator of ageing and metabolism that has been associated with neurodegenerative diseases. However, its role in neurodegeneration is still not well characterized. The PHB complex shows protective or toxic effects in different genetic and physiological contexts, while mitochondrial and cellular stress promote both up and downregulation of PHB expression. With this review we aim to shed light into the complex world of PHB’s function in neurodegeneration by putting together the latest advances in neurodegeneration and mitochondrial homeostasis associated with PHB. A better understanding of the role of PHB in neurodegeneration will add knowledge to neuron deterioration during ageing and help to identify early molecular markers of mitochondrial stress. This review will deepen our understanding of age-related neurodegeneration and provide questions to be addressed, relevant to human health and to improve the life quality of the elderly.

• Adipose Tissue, Brown/metabolism
• Adipose Tissue, White/metabolism
• Animals
• Endothelial Cells
• Endothelium
• Fatty Acids/metabolism
• Female
• Glucose/metabolism
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Prohibitins
• Thermogenesis/genetics
• Transcription Factors/metabolism

• R01 DK088131 NIDDK NIH HHS

• Autophagy
• Lipophagy
• Mitochondria
• Mitochondrial dynamics
• Steroid hormone

• Biological Transport
• Cholesterol/metabolism
• Hormones/metabolism
• Mitochondria/metabolism
• Steroids/metabolism

• PJT-173394 CIHR
• PJX-175420 CIHR

• Animals
• Female
• Male
• Phenotype
• Sex Characteristics

• MC_UU_12012/4 Medical Research Council
• MRC_MC_UU_00014/4 Medical Research Council
• RG/17/12/33167 British Heart Foundation
• 108926/B/15/Z Wellcome Trust
• MR/J001562/1 Medical Research Council
• MC_UU_00014/4 Medical Research Council

Mitochondria are essential for steroidogenesis. In steroidogenic cells, the initiation of steroidogenesis from cholesterol occurs on the matrix side of the inner mitochondrial membrane by the enzyme P450scc. This requires cholesterol import from the cytoplasm through the outer mitochondrial membrane, facilitated by the StAR protein. The subsequent steps leading to P450scc remain elusive. Here we report that the male transgenic mice that expressed a mutant form of a mitochondrial protein prohibitin-1 (PHB1^Tyr114Phe) from the Fabp-4 gene promoter displayed smaller testes, higher testosterone, and lower gonadotropin levels compared with PHB1-expressing and wild-type mice. A subsequent analysis of the testis and Leydig cells from the mice revealed that PHB1 played a previously unknown regulatory role in Leydig cell steroidogenesis. This includes a role in coordinating cell signaling, cholesterol homeostasis, and mitochondrial biology pertaining to steroidogenesis. The implications of our finding are broad as the initial stages of steroidogenesis are indistinguishable across steroidogenic cells.

•

Tyr114Phe-PHB-1 transgenic male mice reveal PHB-1’s role in testosterone production

• Cirrhosis
• Estrogen
• Metabolic dysfunction-associated fatty liver disease
• Nonalcoholic fatty liver disease
• Sex differences
• Steatosis

• Adipocytes/metabolism
• Adipose Tissue, Brown/metabolism
• Animals
• Cells, Cultured
• Energy Metabolism/genetics
• Gene Silencing
• Glucose/metabolism
• Lipid Metabolism/genetics
• Lipolysis/genetics
• Mice
• Mice, Knockout
• Mitochondria/physiology
• Organ Specificity/genetics
• Prohibitins/genetics
• Prohibitins/metabolism
• Thermogenesis/genetics

• R01 DK088131 NIDDK NIH HHS

The mitochondrial prohibitin (PHB) complex, composed of PHB-1 and PHB-2, is an evolutionarily conserved context-dependent modulator of longevity. This extremely intriguing phenotype has been linked to alterations in mitochondrial function and lipid metabolism. The true biochemical function of the mitochondrial PHB complex remains elusive, but it has been shown to affect membrane lipid composition. Recent work, using large-scale biochemical approaches, has highlighted a broad effect of PHB on the C. elegans metabolic network. Collectively, the biochemical data support the notion that PHB modulates, at least partially, worm longevity through the moderation of fat utilisation and energy production via the mitochondrial respiratory chain. Herein, we review, in a systematic manner, recent biochemical insights into the impact of PHB on the C. elegans metabolome.

• ageing
• metabolism
• mitochondrial prohibitin complex

• ERC-2011-StG-281691 European Research Council

• cardiomyopathy
• circulating factor
• inflammation
• mitochondria
• prohibitins
• redox
• shock

• Animals
• Apoptosis/drug effects
• Blood Proteins/metabolism
• Cardiotonic Agents/pharmacology
• Cytokines/metabolism
• Lipopolysaccharides
• Male
• Mice
• Mice, Inbred C57BL
• Myocytes, Cardiac/drug effects
• Prohibitins
• Rats, Sprague-Dawley
• Repressor Proteins/genetics
• Repressor Proteins/metabolism
• Sepsis/drug therapy
• Sepsis/genetics
• Sepsis/metabolism
• Signal Transduction/drug effects
• Rats

• R01 ES028829 NIEHS NIH HHS
• R01 HL122863 NHLBI NIH HHS
• R21 AG057006 NIA NIH HHS
• T32 HL007121 NHLBI NIH HHS
• Department of Defense
• National Institutes of Health
• American Heart Association
• American Association of Immunologists
• East Carolina University

• Diseases
• Immunity
• Metabolism
• mitoUPR

In less than 20 years, three deadly coronaviruses, SARS-CoV, MERS-CoV and SARS-CoV-2, have emerged in human population causing hundreds to hundreds of thousands of deaths. Other coronaviruses are causing epizootic representing a significant threat for both domestic and wild animals. Members of this viral family have the longest genome of all RNA viruses, and express up to 29 proteins establishing complex interactions with the host proteome. Deciphering these interactions is essential to identify cellular pathways hijacked by these viruses to replicate and escape innate immunity. Virus-host interactions also provide key information to select targets for antiviral drug development. Here, we have manually curated the literature to assemble a unique dataset of 1311 coronavirus-host protein–protein interactions. Functional enrichment and network-based analyses showed coronavirus connections to RNA processing and translation, DNA damage and pathogen sensing, interferon production, and metabolic pathways. In particular, this global analysis pinpointed overlooked interactions with translation modulators (GIGYF2-EIF4E2), components of the nuclear pore, proteins involved in mitochondria homeostasis (PHB, PHB2, STOML2), and methylation pathways (MAT2A/B). Finally, interactome data provided a rational for the antiviral activity of some drugs inhibiting coronaviruses replication. Altogether, this work describing the current landscape of coronavirus-host interactions provides valuable hints for understanding the pathophysiology of coronavirus infections and developing effective antiviral therapies.

• Coronavirus
• Interactome
• Protein–protein interactions
• SARS-CoV-2
• Virus-host interactions

Impairment of skeletal muscle function causes disabilities in elderly people. Therefore, in an aged society, prevention and treatment of sarcopenia are important for expanding healthy life expectancy. In addition to aging, adipose tissue disfunction and inflammation also contribute to the pathogenesis of sarcopenia by causing the combined state called ‘sarcopenic obesity’. Muscle quality as well as muscle mass contributes to muscle strength and physical performance. Mitochondria in the skeletal muscles affect muscle quality by regulating the production of energy and reactive oxygen species. A certain portion of the mitochondrial respiratory chain complexes form a higher-order structure called a “supercomplex”, which plays important roles in efficient energy production, stabilization of respiratory chain complex I, and prevention of reactive oxygen species (ROS) generation. Several molecules including phospholipids, proteins, and certain chemicals are known to promote or stabilize mitochondrial respiratory chain supercomplex assembly directly or indirectly. In this article, we review the distinct mechanisms underlying the promotion or stabilization of mitochondrial respiratory chain supercomplex assembly by supercomplex assembly factors. Further, we introduce regulatory pathways of mitochondrial respiratory chain supercomplex assembly and discuss the roles of supercomplex assembly factors and regulatory pathways in skeletal muscles and adipose tissues, believing that this will lead to discovery of potential targets for prevention and treatment of muscle disorders such as sarcopenia.

• adipose tissue
• mitochondria
• respiratory chain supercomplex
• sarcopenia
• skeletal muscle

• CLP-induced sepsis
• HDAC6
• PHB1
• mitochondrial respiratory control rate
• oxidative stress

• Aged
• Animals
• Blotting, Western
• Case-Control Studies
• Cecum/pathology
• Cell Respiration
• China
• Disease Models, Animal
• Female
• Histone Deacetylase 6/metabolism
• Humans
• Ligation
• Male
• Middle Aged
• Mitochondria/metabolism
• Oxidative Stress
• Prohibitins
• Rats
• Rats, Sprague-Dawley
• Repressor Proteins/metabolism
• Sepsis/metabolism
• Sepsis/pathology

Fatty acids are the most major substrate source for adult cardiac energy generation. Prohibitin 2 (PHB2), a highly conserved protein located in mitochondrial inner membrane, plays key roles in cellular energy metabolic homeostasis. However, its functions in regulating cardiac fatty acid metabolism have remained largely unknown. Our study demonstrates that cardiac-specific knockout of Phb2 leads to accumulation of lipid droplets and causes heart failure. Mechanistically, ablation of PHB2 impairs cardiac fatty acid oxidation (FAO) through downregulating carnitine palmitoyltransferase1b (CPT1b), a rate-limiting enzyme of cardiac mitochondrial FAO. Moreover, overexpression of CPT1b alleviates impaired FAO in PHB2-deficient cardiomyocytes. Thus, our study provides direct evidence for the link between PHB2 and cardiac fatty acid metabolism. Our study points out that PHB2 is a potential FAO regulator in cardiac mitochondrial inner membrane, as well as the connection between PHB2 and CPT1b and their relationships to cardiac pathology especially to cardiac fatty acid metabolic disorder.

• aging
• diabetes
• metabolic diseases
• mitochondrial calcium uniporter
• mitochondrial dysfunction
• mitophagy
• obesity

• Aging
• Animals
• Energy Metabolism
• Humans
• Metabolic Diseases/etiology
• Metabolic Diseases/metabolism
• Metabolic Diseases/pathology
• Mitochondria/metabolism
• Mitochondria/pathology
• Reactive Oxygen Species/metabolism
• Signal Transduction

• 17SDG33660407 American Heart Association-American Stroke Association

• adipose tissue
• mitochondria
• obesity

• Animals
• Apoptosis
• Blood Glucose/metabolism
• Calcium/metabolism
• Calcium Signaling/drug effects
• Cytokines/metabolism
• Diabetes Mellitus/metabolism
• Diabetes Mellitus/pathology
• Humans
• Insulin-Secreting Cells/metabolism
• Insulin-Secreting Cells/pathology
• Lipid Metabolism
• Mitochondria/metabolism
• Mitochondria/pathology
• Prohibitins
• Repressor Proteins/metabolism

Ovarian cancer (OC) is the most lethal gynecologic cancer characterized by an elevated apoptosis resistance that, potentially, leads to chemo-resistance in the recurrent disease. Mitochondrial oxidative phosphorylation was found altered in OC, and mitochondria were proposed as a target for therapy. Molecular evidence suggests that the deregulation of mitochondrial biogenesis, morphology, dynamics, and apoptosis is involved in carcinogenesis. However, these mitochondrial processes remain to be investigated in OC. Eighteen controls and 16 OC tissues (serous and mucinous) were collected. Enzymatic activities were performed spectrophotometrically, mitochondrial DNA (mtDNA) content was measured by real-time-PCR, protein levels were determined by Western blotting, and mitochondrial number and structure were measured by electron microscopy. Statistical analysis was performed using Student’s t-test, Mann-Whitney U test, and principal component analysis (PCA). We found, in OC, that increased mitochondrial number associated with increased peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) and mitochondrial transcription factor A (TFAM) protein levels, as well as mtDNA content. The OC mitochondria presented an increased maximum length, as well as reduced cristae width and junction diameter, associated with increased optic atrophy 1 protein (OPA1) and prohibitin 2 (PHB2) protein levels. In addition, in OC tissues, augmented cAMP and sirtuin 3 (SIRT3) protein levels were observed. PCA of the 25 analyzed biochemical parameters classified OC patients in a distinct group from controls. We highlight a “mitochondrial signature” in OC that could result from cooperation of the cAMP pathway with the SIRT3, OPA1, and PHB2 proteins.

• OPA1
• SIRT3
• cAMP
• mitochondria
• mitochondrial biogenesis
• ovarian cancer
• oxidative phosphorylation system (OXPHOS)
• prohibitins

Adipocytes and macrophages, the two major constituents of adipose tissue, exhibit sex differences and work in synergy in adipose tissue physiology and pathophysiology, including obesity-linked insulin resistance and metabolic dysregulation. Sex steroid hormones play a major role in sex differences in adipose tissue biology. However, our knowledge of the molecules that mediate these effects in adipose tissue remains limited. Consequently, it remains unclear whether these effector molecules in different adipose and immune cell types are distinct or if there are also pleiotropic effectors. Recently, a protein named prohibitin (PHB) with cell compartment- and tissue-specific functions has been found to play a role in sex differences in adipose and immune functions. Transgenic (Tg) mouse models overexpressing PHB (PHB-Tg) and a phospho-mutant PHB (mPHB-Tg) from the fatty acid binding protein-4 (Fabp-4) gene promoter display sex-neutral obesity; however, obesity-related insulin resistance and metabolic dysregulation are male-specific. Intriguingly, with aging, the male PHB-Tg mice developed hepatic steatosis and subsequently liver tumors whereas the male mPHB-Tg mice developed lymph node tumors and splenomegaly. Unlike the male transgenic mice, the female PHB-Tg and mPHB-Tg mice remain protected from obesity-related metabolic dysregulation and tumor development. In conclusion, the sex-dimorphic metabolic and immune phenotypes of PHB-Tg and mPHB-Tg mice have revealed PHB as a pleiotropic effector of sex differences in adipose and immune functions. In this mini-review, we will discuss the pleiotropic attributes of PHB and potential mechanisms that may have contributed to the sex-dimorphic metabolic phenotypes in PHB-Tg and mPHB-Tg mice, which warrant future research. We propose that PHB is a prime candidate for a pleiotropic mediator of sex differences in adipose and immune functions in both physiology and pathophysiology, including obesity, insulin resistance, and metabolic dysregulation.

• Androgen receptors
• Estrogen receptors
• Mitochondria
• O-GlcNAc transferase
• Sex steroids
• Transgenic mice

• Sex differences
• X chromosome inactivation
• epigenetics
• mitochondria
• sex steroids

• Animals
• Body Fat Distribution
• Epigenomics
• Female
• Genes, X-Linked
• Gonadal Steroid Hormones/metabolism
• Humans
• Immune System Diseases/genetics
• Immune System Diseases/metabolism
• Male
• Metabolic Diseases/genetics
• Metabolic Diseases/metabolism
• Mice
• Mitochondria/physiology
• Mitochondrial Proteins/genetics
• Mitochondrial Proteins/metabolism
• Mitochondrial Proteins/physiology
• Prohibitins
• Repressor Proteins/metabolism
• Repressor Proteins/physiology
• Sex Characteristics
• Sex Factors

• Research Manitoba
• Winnipeg Health Sciences Centre Foundation
• Natural Sciences and Engineering Research Council of Canada

Prohibitin 1 (PHB1) and prohibitin 2 (PHB2) are proteins that are ubiquitously expressed, and are present in the nucleus, cytosol, and mitochondria. Depending on the cellular localization, PHB1 and PHB2 have distinctive functions, but more evidence suggests a critical role within mitochondria. In fact, PHB proteins are highly expressed in cells that heavily depend on mitochondrial function. In mitochondria, these two proteins assemble at the inner membrane to form a supra-macromolecular structure, which works as a scaffold for proteins and lipids regulating mitochondrial metabolism, including bioenergetics, biogenesis, and dynamics in order to determine the cell fate, death, or life. PHB alterations have been found in aging and cancer, as well as neurodegenerative, cardiac, and kidney diseases, in which significant mitochondrial impairments have been observed. The molecular mechanisms by which prohibitins regulate mitochondrial function and their role in pathology are reviewed and discussed herein.

• apoptosis
• mitochondria
• mitochondrial dynamics
• oxidative phosphorylation
• prohibitins

• Animals
• Humans
• Mitochondria/metabolism
• Mitochondria/ultrastructure
• Mitochondrial Diseases/metabolism
• Organelle Biogenesis
• Oxidative Phosphorylation
• Prohibitins
• Repressor Proteins/metabolism
• Unfolded Protein Response

• adipose tissue
• adipose-immune crosstalk
• hyperinsulinemia
• insulin resistance
• meta-inflammation
• obesity-linked cancer models

• RGPIN-2017-04962 Natural Sciences and Engineering Research Council of Canada

• mitochondria
• oxidative phosphorylation
• mitochondrial unfolded protein response
• diabetes
• insulin resistance

• Animals
• Humans
• Insulin Resistance/physiology
• Metabolic Diseases/metabolism
• Mitochondria/metabolism
• Oxidative Phosphorylation
• Signal Transduction/physiology
• Unfolded Protein Response/physiology

Recently, we have developed a novel transgenic mouse model by overexpressing prohibitin (PHB) in adipocytes, which developed obesity due to upregulation of mitochondrial biogenesis in adipocytes, hence named “Mito-Ob.” Interestingly, only male Mito-Ob mice developed obesity-related impaired glucose homeostasis and insulin sensitivity, whereas female Mito-Ob mice did not. The observed sex differences in metabolic dysregulation suggest a potential involvement of sex steroids. Thus, the main aim of this study is to investigate the role of sex steroids on the overall phenotype of Mito-Ob mice through gonadectomy, as well as direct effect of sex steroids on adipocytes from Mito-Ob mice in vitro.

Mito-Ob mice and wild-type CD-1 mice were gonadectomized at 12 weeks of age. Age- and sex-matched sham-operated mice were used as controls. Body weight, white adipose tissue, glucose tolerance, and insulin sensitivity were analyzed 3 months post-surgery. Differentiation of adipocytes isolated from female and male Mito-Ob mice were studied with and without sex steroids.

Gonadectomy significantly reduced body weight in Mito-Ob mice compared with sham-operated mice, whereas the opposite trend was observed in wild-type mice. These changes occurred independent of food intake. A corresponding decrease in adipose tissue weight was found in gonadectomized Mito-Ob mice, but depot-specific differences were observed in male and female. Gonadectomy improved glucose tolerance in male wild-type and Mito-Ob mice, but the effect was more pronounced in wild-type mice. Gonadectomy did not alter insulin sensitivity in male Mito-Ob mice, but it was improved in male wild-type mice. In primary cell cultures, testosterone inhibited adipocyte differentiation to a lesser extent in male Mito-Ob preadipocytes compared with the wild-type mice. On the other hand, preadipocytes from female wild-type mice showed better differentiation potential than those from female Mito-Ob mice in the presence of 17β-estradiol.

PHB requires sex steroids for the development of obese phenotype in Mito-Ob mice, which differentially affect glucose homeostasis and insulin sensitivity in male and female. It appears that PHB plays sex- and adipose depot-specific roles and involves additional factors. In vitro studies suggested that PHB differently influenced adipocyte differentiation in the presence and absence of sex steroids. Overall, this study along with available information in the literature indicated that a multifaceted relationship exists between PHB and sex steroids, which may work in a cell/tissue type- and sex-specific manner.

• 17β-estradiol
• Adipocyte differentiation
• Obesity
• Prohibitin
• Sex differences
• Testosterone
• Transgenic mice

Melanoma is responsible for most deaths among skin cancers and conventional and palliative care chemotherapy are limited due to the development of chemoresistance. We used proteomic analysis to identify cellular responses that lead to chemoresistance of human melanoma cell lines to cisplatin. A systems approach to the proteomic data indicated the participation of specific cellular processes such as oxidative phosphorylation, mitochondrial organization and homeostasis, as well as the unfolded protein response (UPR) to be required for the survival of cells treated with cisplatin. Prohibitin (PHB) was among the proteins consistently accumulated, interacting with the functional clusters associated with resistance to cisplatin. We showed PHB accumulated at different levels in melanoma cell lines under stressing stimuli, such as (i) treatment with temozolomide (TMZ), dacarbazine (DTIC) and cisplatin; (ii) serum deprivation; (iii) tunicamycin, an UPR inducer. Prohibitin accumulated in the mitochondria of melanoma cells after cisplatin and tunicamycin treatment and its de novo accumulation led to chemoresistance melanoma cell lines. In contrast, PHB knock-down sensitized melanoma cells to cisplatin and tunicamycin treatment. We conclude that PHB participates in the survival of cells exposed to different stress stimuli, and can therefore serve as a target for the sensitization of melanoma cells to chemotherapy.

• cisplatin
• melanoma
• mitochondria
• prohibitin
• tunicamycin

• 14-3-3 protein
• adipocyte
• adipogenesis
• alternative splicing
• scaffold protein

Prohibitin is a pleiotropic protein that has roles in fundamental cellular processes, such as cellular proliferation and mitochondrial housekeeping, and in cell- or tissue-specific functions, such as adipogenesis and immune cell functions. The different functions of prohibitin are mediated by its cell compartment-specific attributes, which include acting as an adaptor molecule in membrane signaling, a scaffolding protein in mitochondria, and a transcriptional co-regulator in the nucleus. However, the precise relationship between its distinct cellular localization and diverse functions remain largely unknown. Accumulating evidence suggests that the phosphorylation of prohibitin plays a role in a number of cell signaling pathways and in intracellular trafficking. Herein, we discuss the known and potential importance of the site-specific phosphorylation of prohibitin in regulating these features. We will discuss this in the context of new evidence from tissue-specific transgenic mouse models of prohibitin, including a mutant prohibitin lacking a crucial tyrosine phosphorylation site. We conclude with the opinion that prohibitin can be used as a potential target for tyrosine kinase signal transduction-targeting therapy, including in insulin, growth factors, and immune signaling pathways.

• Boleophthalmus pectinirostris
• Mitochondria
• Prohibitin
• Spermatogenesis

• Amino Acid Sequence
• Animals
• Base Sequence
• Fishes/metabolism
• Male
• Mitochondria/metabolism
• Phylogeny
• Prohibitins
• RNA, Messenger/genetics
• RNA, Messenger/metabolism
• Repressor Proteins/chemistry
• Repressor Proteins/genetics
• Repressor Proteins/metabolism
• Spermatogenesis/physiology
• Testis/metabolism

Polycystic ovary syndrome (PCOS) is a prevalent endocrine disorder and the most common cause of female infertility. However, its etiology and underlying mechanisms remain unclear. Here we report that a transgenic obese mouse (Mito-Ob) developed by overexpressing prohibitin in adipocytes develops polycystic ovaries. Initially, the female Mito-Ob mice were equally fertile to their wild-type littermates. The Mito-Ob mice began to gain weight after puberty, became significantly obese between 3-6 months of age, and ∼25% of them had become infertile by 9 months of age. Despite obesity, female Mito-Ob mice maintained glucose homeostasis and insulin sensitivity similar to their wild-type littermates. Mito-Ob mice showed morphologically distinct polycystic ovaries and elevated estradiol, but normal testosterone and insulin levels. Histological analysis of the ovaries showed signs of impaired follicular dynamics, such as preantral follicular arrest and reduced number, or absence, of corpus luteum. The ovaries of the infertile Mito-Ob mice were closely surrounded by periovarian adipose tissue, suggesting a potential role in anovulation. Collectively, these data suggest that elevated estradiol and obesity per se might lead to anovulation and polycystic ovaries independent of hyperinsulinemia and hyperandrogenism. As obesity often coexists with other abnormalities known to be involved in the development of PCOS such as insulin resistance, compensatory hyperinsulinemia and hyperandrogenism, the precise role of these factors in PCOS remains unclear. Mito-Ob mice provide an opportunity to study the effects of obesity on anovulation and ovarian cyst formation independent of the major drivers of obesity-linked PCOS.

Summary: Obesity-related overgrowth of periovarian adipose tissue and elevated estradiol levels cause anovulation and ovarian cyst formation in mice, independent of hyperinsulinemia and hyperandrogenism.

• Cystic ovary
• Female infertility
• Periovarian adipose tissue
• Transgenic models

• Adipocyte
• adipose-immune crosstalk
• immune cell
• mitochondria
• pleiotropic protein
• sex dimorphic

Proteins are the major constituents of muscle and are key molecules regulating the metabolic changes during conversion of muscle to meat. Brazil is one of the largest exporters of beef and most Brazilian cattle are composed by zebu (Nellore) genotype. Bos indicus beef is generally leaner and tougher than Bos taurus such as Angus. The aim of this study was to compare the muscle proteomic and phosphoproteomic profile of Angus and Nellore. Seven animals of each breed previously subjected the same growth management were confined for 84 days. Proteins were extracted from Longissimus lumborum samples collected immediately after slaughter and separated by two-dimensional electrophoresis. Pro-Q Diamond stain was used in phosphoproteomics. Proteins identification was performed using matrix assisted laser desorption/ionization time-of-flight mass spectrometry. Tropomyosin alpha-1 chain, troponin-T, myosin light chain-1 fragment, cytoplasmic malate dehydrogenase, alpha-enolase and 78 kDa glucose-regulated protein were more abundant in Nellore, while myosin light chain 3, prohibitin, mitochondrial stress-70 protein and heat shock 70 kDa protein 6 were more abundant in Angus (P<0.05). Nellore had higher phosphorylation of myosin regulatory light chain-2, alpha actin-1, triosephosphate isomerase and 14-3-3 protein epsilon. However, Angus had greater phosphorylation of phosphoglucomutase-1 and troponin-T (P<0.05). Therefore, proteins involved in contraction and muscle organization, myofilaments expressed in fast or slow-twitch fibers and heat shock proteins localized in mitochondria or sarcoplasmic reticulum and involved in cell flux of calcium and apoptosis might be associated with differences in beef quality between Angus and Nellore. Furthermore, prohibitin appears to be a potential biomarker of intramuscular fat in cattle. Additionally, differences in phosphorylation of myofilaments and glycolytic enzymes could be involved with differences in muscle contraction force, susceptibility to calpain, apoptosis and postmortem glycolysis, which might also be related to differences in beef quality among Angus and Nellore.

Prohibitin (PHB) is a highly conserved protein implicated in various cellular functions including proliferation, apoptosis, tumor suppression, transcription, and mitochondrial protein folding. However, its function in diabetic cardiomyopathy (DCM) is still unclear. In vivo, type 2 diabetic rat model was induced by using a high-fat diet and low-dose streptozotocin. Overexpression of the PHB protein in the model rats was achieved by injecting lentivirus carrying PHB cDNA via the jugular vein. Characteristics of type 2 DCM were evaluated by metabolic tests, echocardiography and histopathology. Rats with DCM showed severe insulin resistance, left ventricular dysfunction, fibrosis and apoptosis. PHB overexpression ameliorated the disease. Cardiofibroblasts (CFs) and H9c2 cardiomyoblasts were used in vitro to investigate the mechanism of PHB in altered function. In CFs treated with HG, PHB overexpression decreased expression of collagen, matrix metalloproteinase activity, and proliferation. In H9c2 cardiomyoblasts, PHB overexpression inhibited apoptosis induced by HG. Furthermore, the increased phosphorylation of extracellular signal–regulated kinase (ERK) 1/2 was significantly decreased and the inhibited phosphorylation of Akt was restored in DCM. Therefore, PHB may be a new therapeutic target for human DCM.

• Pathology Section
• apoptosis
• diabetic cardiomyopathy
• myocardial fibrosis
• prohibitin

• adipose–immune interaction
• autoimmune diabetes.
• cancer
• inflammation
• obesity
• sexually dimorphic

• Adiposity/genetics
• Adiposity/physiology
• Animals
• Cell Nucleus/metabolism
• Diabetes Mellitus, Type 1/genetics
• Diabetes Mellitus, Type 1/immunology
• Diabetes Mellitus, Type 1/metabolism
• Humans
• Inflammation/genetics
• Inflammation/immunology
• Inflammation/metabolism
• Obesity/genetics
• Obesity/immunology
• Obesity/metabolism
• Prohibitins
• Repressor Proteins/genetics
• Repressor Proteins/metabolism
• Signal Transduction/genetics
• Signal Transduction/immunology
• Signal Transduction/physiology

Sex differences are known to exist in adipose and immune functions in the body, and sex steroid hormones are known to be involved in sexually dimorphic biological and pathological processes related to adipose-immune interaction. However, our knowledge of proteins that mediate such differences is poor. Two novel obese mice models, Mito-Ob and m-Mito-Ob, that have been reported recently have revealed an unexpected role of a pleiotropic protein, prohibitin (PHB), in sex differences in adipose and immune functions. This discovery points towards a role of pleiotropic proteins and their potential interplay with sex steroid hormones in mediating sexually dimorphic adipose-immune interaction.

• Adipose-immune interaction
• Inflammation
• Insulin resistance
• Metabolic dysregulation
• Obesity
• Pleiotropic proteins

• Animals
• Carcinoma, Hepatocellular/etiology
• Disease Models, Animal
• Female
• Gene Expression Regulation, Neoplastic
• Insulin Resistance
• Liver Neoplasms/etiology
• MAP Kinase Signaling System
• Male
• Mice
• Mice, Obese
• Non-alcoholic Fatty Liver Disease/etiology
• Obesity/genetics
• Obesity/immunology
• Obesity/metabolism
• Prohibitins
• Repressor Proteins/deficiency
• STAT3 Transcription Factor/metabolism
• Sex Characteristics