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Review
. 2018 Feb 19;28(4):R170-R185.
doi: 10.1016/j.cub.2018.01.004.

Mitophagy and Quality Control Mechanisms in Mitochondrial Maintenance

Sarah Pickles  1 , Pierre Vigié  2 , Richard J Youle  3
Affiliations
Review

Mitophagy and Quality Control Mechanisms in Mitochondrial Maintenance

Sarah Pickles et al. Curr Biol. .

Abstract

The maintenance of a healthy and functional mitochondrial network is critical during development as well as throughout life in the response to physiological adaptations and stress conditions. Owing to their role in energy production, mitochondria are exposed to high levels of reactive oxygen species, making them particularly vulnerable to mitochondrial DNA mutations and protein misfolding. Given that mitochondria are formed from proteins encoded by both nuclear and mitochondrial genomes, an additional layer of complexity is inherent in the coordination of protein synthesis and the mitochondrial import of nuclear-encoded proteins. For these reasons, mitochondria have evolved multiple systems of quality control to ensure that the requisite number of functional mitochondria are present to meet the demands of the cell. These pathways work to eliminate damaged mitochondrial proteins or parts of the mitochondrial network by mitophagy and renew components by adding protein and lipids through biogenesis, collectively resulting in mitochondrial turnover. Mitochondrial quality control mechanisms are multi-tiered, operating at the protein, organelle and cell levels. Herein, we discuss mitophagy in different physiological contexts and then relate it to other quality control pathways, including the unfolded protein response, shedding of vesicles, proteolysis, and degradation by the ubiquitin-proteasome system. Understanding how these pathways contribute to the maintenance of mitochondrial homeostasis could provide insights into the development of targeted treatments when these systems fail in disease.

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Figures

Figure 1
Figure 1. Functional domains of autophagy receptor proteins that operate in mitophagy
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 elucidated. CC, coiled-coil domain; LIR, LC3-interactions region; 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; SKITCH, SKIP carboxyl homology domain; NLS, nuclear localization signals; KIR. Keap interacting region.
Figure 2
Figure 2. PINK1 is stabilized on the outer mitochondrial membrane upon mitochondrial stress and triggers mitophagy
(A) In basal conditions, PINK1 is imported into the mitochondria in a TOM and TIM complex-dependent manner. PINK1 undergoes proteolytic cleavage by the matrix protein MPP and PARL, located in the IMM. Processed PINK1 is then targeted to the proteasome for degradation. (B) Upon mitochondrial stress, PINK1 import is compromised and cannot be processed by PARL and is stabilized on the OMM, where it phosphorylates both Ubiquitin (red circle) and Parkin. Parkin is then recruited to phosphorylated ubiquitin (green circle) attached to various mitochondrial substrate proteins (S) and is itself phosphorylated by PINK1.
Figure 3
Figure 3. A feedback loop fates mitochondria for degradation
In basal conditions, PINK1 is imported into mitochondria, processed, and degraded by the proteasome. (1) Under mitochondrial stress, PINK1 is stabilized to the outer mitochondrial membrane where it phosphorylates ubiquitin (red circle) located on OMM proteins substrates (S). Parkin has a high affinity for phospho-ubiquitin (green circle) and translocates from the cytosol to the mitochondrial surface. (2) PINK1 activates Parkin by phosphorylation of serine 65 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 which amplifies phospo-ubiquitin.
Figure 4
Figure 4. Modelling the impact of mitophagy on mitochondrial protein turnover
Within a cell mitochondrial proteins can be degraded by mitophagy, eliminating either parts or the whole organelle, or by OMMAD, proteases and 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 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. Mitochondrial protein 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. In 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 of the total rate of turnover of each protein. More drastic rate changes are observed in proteins 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. 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 mitochondrial protein z, x, y.
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