Figure 2.

Molecular determinants of mitochondrial quality-control networks. Mitochondria are dynamic organelles that are continuously remodelled by fusion and fission events. Fusion requires the joining of both the inner and outer mitochondrial membranes of two mitochondria. Mitofusin 1 (MFN1) and mitofusin 2 (MFN2) carry out the initial joining of the outer membrane fusion, whereas OPA1 mediates the fusion of the inner membrane. Mitochondrial fission is mediated by DRP1 and FIS1; DRP1 oligomerizes into 8–12 subunit chains and is recruited to mitochondria via the adaptor FIS1. This recruitment allows the full oligomerisation of DRP1 into spiral chains that wrap around the mitochondria and, by constriction, causes mitochondrial fission. In this figure, fission is shown as a means to selectively eliminate damaged mitochondrial components by packing them in one of the fission products, and it has been proposed to involve the asymmetrical segregation of OPA1 (Ref. 5). In this context, fission produces metabolically different daughter units that may either maintain (red) or lose (grey) an intact membrane potential. Depolarised mitochondria are targeted to degradation by autophagy (mitophagy) through a mechanism that is still poorly defined. Here, we illustrate two possibilities: (1) the presence of proteins associated with mitochondrial membranes, such as the mammalian BNIP3L/NIX (Ref. 109, 110), and the yeast proteins Uth1p (Ref. 111) and Aup1 (Ref. 112), which are involved in the direct entrapment of mitochondria by autophagosomes; (2) the activity of E3 ligases, such as LISTERIN (Ref. 113), MULAN (Ref. 114) and Parkin (Refs 28, 115), which might regulate the conjugation of monoubiquitin (Ub) or polyubiquitin chains to an exposed mitochondrial protein, thereby targeting the organelle to autophagic degradation. p62 and NBR1 are autophagic receptors that bind both Ub and ATG8/LC3 on the phagophore (Ref. 116), which might constitute the mechanistic link between mitochondrial ubiquitylation and mitophagy. The mTOR signalling pathway acts as a major positive modulator of mitochondrial metabolism and biogenesis. We propose that the inhibition of mTORC1 upon mitochondrial damage caused by loss of ATP and consequential activation of AMPK, might be crucial to ensure an enhancement of the autophagic degradation of defective mitochondria. Abbreviations: AMPK, AMP-activated protein kinase; Aup1p, yeast mitochondrial protein phosphatase homologue; BNIP3L/NIX, BCL2/adenovirus E1B 19 kDa protein-interacting protein 3-like; LC3, light chain 3 protein; LKB1, serine/threonine-protein kinase 11; mTOR, mammalian target of rapamycin; mTORC1, mTOR complex 1; NBR1, next to BRCA1 gene 1 protein; OM, outer membrane; OPA1, optic atrophy 1; Uth1p, yeast outer mitochondrial membrane protein.