1. Mitophagy and Quality Control Mechanisms in Mitochondrial Maintenance
Sarah Pickles, Pierre Vigié, Richard J. Youle 
Current Biology 
Volume 28, Issue 4, Pages R170-R185 (February 2018)
DOI: /j.cub
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2. Figure 1
Functional domains of autophagy receptor proteins that operate in mitophagy.
The mitophagy receptors Atg32, NIX and BNIP3 are localized to the mitochondrial outer membrane and schematics of their functional domains are depicted: AIM, Atg8 family interacting motif; TMD, transmembrane domain; LIR, LC3-interacting region. Autophagy receptor proteins involved in mitophagy are shown bound to ubiquitinated mitochondrial substrates (S) and similarly their functional domains are shown: CC, coiled-coil domain; UBAN, ubiquitin binding in ABIN and NEMO domain; ZF, zinc-finger domain; PB1, Phox and Bem1 domain; ZZ, ZZ-type zinc finger domain; FW, four tryptophan domain; UBA, ubiquitin associated domain; SKICH, SKIP carboxyl homology domain; NLS, nuclear localization signals; KIR, Keap interacting region.
Current Biology  , R170-R185DOI: ( /j.cub )
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3. Figure 2
PINK1 is stabilized on the outer mitochondrial membrane upon mitochondrial stress and triggers mitophagy.
(A) Under basal conditions, PINK1 is imported into mitochondria in a manner dependent on the multiprotein TOM and TIM complexes. PINK1 undergoes proteolytic cleavage by the matrix protein MPP and by the inner mitochondrial membrane protein PARL. Processed PINK1 is then targeted to the proteasome for degradation. (B) Upon mitochondrial stress or damage, PINK1 import is compromised. PINK1 therefore cannot be processed by PARL and is stabilized on the outer mitochondrial membrane, where it phosphorylates both Parkin and ubiquitin (red circles). Parkin is then recruited to phosphorylated ubiquitin (green circles) attached to various mitochondrial substrate proteins (S) and is itself phosphorylated by PINK1. IMM, inner mitochondrial membrane; IMS, intermembrane space; OMM, outer mitochondrial membrane.
Current Biology  , R170-R185DOI: ( /j.cub )
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4. Figure 3 A feedback loop in mitochondrial degradation.
Under basal conditions, PINK1 is imported into mitochondria, processed, and degraded by the proteasome. (1) Under mitochondrial stress, PINK1 is stabilized at the OMM where it phosphorylates ubiquitin (red circle) bound to OMM protein substrates (S). Parkin has a high affinity for phospho-Ub (green circle) and translocates from the cytosol to the mitochondrial surface. (2) PINK1 activates Parkin by phosphorylation of Ser65 enhancing its E3 ubiquitin ligase activity. (3 and 4) Activated Parkin ubiquitinates OMM protein substrates and PINK1 phosphorylates ubiquitin leading to further Parkin recruitment and activation, resulting in a feedback loop that amplifies phospho-Ub.
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5. Figure 4
Modelling the impact of mitophagy on mitochondrial protein turnover.
Within a cell, mitochondrial proteins can be degraded by mitophagy — eliminating either part or all of the organelle — or by outer mitochondrial membrane-associated degradation (OMMAD), proteases and mitochondria-derived vesicles (MDVs), which when summed together constitute a protein’s total turnover rate, disregarding the rate of replacement via mitochondrial biogenesis. To hypothesize the contribution of mitophagy to mitochondrial protein turnover, we assume that the turnover of a given protein is equal to its protein turnover in addition to turnover via mitophagy (mitophagy turnover; mt). In the following model, a cell contains 100 mitochondria, each with 1 copy of proteins x, y, and z. These mitochondrial proteins have turnover rates xt, yt, and zt, corresponding to low (5 protein copies/hour), intermediate (10 protein copies/hour) and high (50 protein copies/hour) turnover rates, respectively. While protein turnover rates remain constant, the rate of mitophagy is altered. Under basal conditions, one can assume a low rate of mitophagy (mt), 1 organelle per hour. Physiological and pathological stimuli could increase the rate of mitophagy to 10 organelles per hour (medium mitophagy) or 50 organelles per hour (fast mitophagy). Summation of the mitochondrial and protein turnover rate would have differential effects on the total rate of turnover of each protein. More drastic rate changes are observed for proteins that are turned over more slowly and the range of turnover rates would tighten. Nonetheless, protein turnover rates remain distinct even in scenarios with extremely high rates of mitophagy. The heat map plots total turnover rate (protein copies degraded per hour per 100 mitochondria) as a function of protein turnover (x-axis) versus mitophagy turnover (y-axis) for the mitochondrial proteins x, y, z.
Current Biology  , R170-R185DOI: ( /j.cub )
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