Mitophagy in the aging nervous system

Abstract

Aging is characterised by the progressive accumulation of cellular dysfunction, stress, and inflammation. A large body of evidence implicates mitochondrial dysfunction as a cause or consequence of age-related diseases including metabolic disorders, neuropathies, various forms of cancer and neurodegenerative diseases. Because neurons have high metabolic demands and cannot divide, they are especially vulnerable to mitochondrial dysfunction which promotes cell dysfunction and cytotoxicity. Mitophagy neutralises mitochondrial dysfunction, providing an adaptive quality control strategy that sustains metabolic homeostasis. Mitophagy has been extensively studied as an inducible stress response in cultured cells and short-lived model organisms. In contrast, our understanding of physiological mitophagy in mammalian aging remains extremely limited, particularly in the nervous system. The recent profiling of mitophagy reporter mice has revealed variegated vistas of steady-state mitochondrial destruction across different tissues. The discovery of patients with congenital autophagy deficiency provokes further intrigue into the mechanisms that underpin neural integrity. These dimensions have considerable implications for targeting mitophagy and other degradative pathways in age-related neurological disease.

Keywords: aging; autophagy; brain; disease; longevity; mitochondria; mitophagy.

FIGURE 1

Generalised autophagy logistics: macroautophagy, CMA and microautophagy. (A)–Non-selective macroautophagy: ATG proteins participate in phagophore biogenesis and expansion, generating a double membrane structure that encapsulates portions of cytoplasmic matter. Leading edges of the expanding phagophore undergo abscission to form the autophagosome, which matures and eventually fuses with an acidic endolysosome to yield an autolysosome. Cargo is degraded by hydrolytic enzymes originating from the lysosome and is recycled to fuel cellular anabolism and signalling. (B)–Chaperone mediated autophagy (CMA): CMA involves the selective sequestration of proteins containing a KFERQ-motif. Here, cytosolic proteins are recogniced by chaperones that mediate the transportation to the lysosomal membrane, where the transmembrane receptor LAMP-2 binds to and translocates the cargo into the lysosomal lumen for elimination. (C)–Selective and non-selective microautophagy. Cytosolic cargo is degraded selectively or non-selectively via lysosomal or late endosomal membrane invagination and internalisation. Once internalised, lysosomal hydrolytic enzymes degrade the cargo.

FIGURE 2

Ubiquitin dependent and independent mitophagy. Upper panel: The best studied ubiquitin-dependent mitophagy mechanism is the PINK1-Parkin-dependent pathway. Briefly, extreme chemical stress promotes mitochondrial damage which triggers PINK1 stabilisation and activation on the outer mitochondrial membrane (OMM). PINK1 recruits ubiquitin and the E3 ligase Parkin to the mitochondria and phosphorylates their respective Ser65 residues. Feed-forward amplification cycle signals result in coating of damaged mitochondria with ubiquitin, which promotes the recruitment of autophagy adaptors, phagophore biogenesis and engulfment. Engulfed mitochondria within autophagosomes are destroyed upon fusion with acidic endolysosomal subcompartment. Although PINK1 and Parkin promote mitochondrial clearance in cultured proliferating cells, several studies demonstrate this pathway does not regulate physiological mitophagy within tissues. Lower panel: Ubiquitin-independent mitophagy. Basal and programmed mitophagy occur in tissues, likely in response to altered metabolic demands, states of insults that damage mitochondria. Phagophores form on mitochondria through the interaction of selective autophagy receptors (e.g., NIX, FUNDC1) with ATG8 proteins. NIX/BNIP3L is especially important during programmed mitophagy and metabolic maturation. NIX/BNIP3L phosphorylation enhances its association with ATG8 proteins. Loss of NIX/BNIP3L alters physiological mitophagy in the retina and reticulocytes. Several of the most promising therapeutic strategies to modulate mitophagy operate via ubiquitin-independent mechanisms.