Peroxisomes synthesize and degrade a wide variety of cellular compounds. Through α- and β-oxidations, specific long-chain, very-long-chain, and 3-methyl-branched-chain fatty acids are degraded. These processes may occur entirely within the organelle or may involve participation of other organelles - e.g., mitochondria. The notion that peroxisomes shuttle metabolites for continued processing and/or anaplerotic metabolism is part of an emergent theme for the organelle; specifically, that it is integrated into a variously interacting endomembrane system responsible for a number of critical cellular processes.
The peroxisome’s handling of hydrogen peroxide, a reactive oxygen species produced by oxidative reactions occurring within the organelle, also bears on this point. Under most conditions, hydrogen peroxide is produced and immediately processed by the organelle’s resident marker enzyme, catalase. However, conditions exist in which the balance of hydrogen peroxide production is upset, and the potentially toxic metabolite accumulates[3-7]. As discussed further below, such phenomena set cells on a pro-aging program with potentially important health ramifications.
Other catabolic functions carried out by peroxisomes include degradation of polyamines, glyoxylate, certain amino acids, and several xenobiotics. In addition, the organelle breaks down the arachidonic acid derivatives known as eicosanoids. Eicosanoids are critically important signaling molecules which exert tremendous control over inflammatory reactions. Among the arachidonic acid derivatives under consideration here are prostaglandins, thromboxanes, leukotrienes, and prostacyclins. These compounds elicit broad ranging inflammatory reactions depending on concentration and location.
Included among the activities engendered by these molecules are modulating vasoconstriction/vasodilation and smooth muscle contraction/relaxation, controlling platelet aggregation, regulating hormone release/metabolism, and initiating pyrogenic (i.e., febrile) responses. And these examples only partially represent the broad physiological effects elicited by eicosanoids. The important point is that through their ability to be metabolized by peroxisomes - organelle function is linked to the inflammatory response.
Inflammation could not be a more popular topic in current medical research. There is a sense in the clinical community that inflammation plays a major role in aging and in chronic diseases. Indeed, the term “inflammaging” has been coined and is in use. Targeting inflammation is popularly seen as a major strategy to combat these processes. Specific pathways involving the presence of reactive oxygen species and chronic activation of inflammatory pathways are examined further below.
Peroxisomes contain enzymes which contribute to the synthesis of critical cellular constituents including bile acids, ether phospholipids, and docosahexaenoic acids, among others. Bile acids, derived from cholesterol, are important molecules involved in digestion through their ability to emulsify fats. Ether phospholipids, including plasmalogens, represent a vital class of membrane protective molecules, found throughout cells of the body. Myelin, the insulating layer of nerve sheaths, contains plasmalogens; absence of the ether phospholipid is associated with progressive neurological impairment. Docosahexaenoic acids, peroxisomally produced omega-3 fatty acids, are the pivotal precursors of resolvins (“resolution-phase interaction products”), maresins (“macrophage mediator in resolving inflammation”), and protectins (formerly called “neuroprotectins”)[10-12]. These molecules possess potent anti-inflammatory, inflammatory resolving, and immunoregulatory activities. Importantly, conversion of docosahexaenoic acids to these biologically active mediators is accelerated by non-steroidal anti-inflammatory drugs, including aspirin, which inhibits the cyclooxygenase-2 enzyme.