Mechanisms and Roles of Mitophagy

Abstract

Mitochondria are highly dynamic organelles that provide essential metabolic functions and represent the major bioenergetic hub of eukaryotic cells. Mitochondrial dysfunctions are implicated in numerous diseases. Therefore, maintenance of a healthy pool of mitochondria is required for cellular function and survival. Mitochondrial quality control is secured by several mechanisms that act at different levels: proteases and chaperones, the ubiquitin‐proteasome system (UPS) and mitophagy. Multiple mitophagy programs either operate independently or undergo crosstalk and require modulated receptor activities in the mitochondrial membranes. In mammals, different mitophagy effectors have been characterised, such as the receptors NIX, BNIP3, FUNDC1, BCL2L13, Prohibitin2, cardiolipin and PINK1/Parkin pathway.

Key Concepts

  • Mitophagy is a process that degrades mitochondria selectively via autophagy.
  • Mitophagy operates at the organelle scale.
  • Proteases, chaperones and ubiquitin‐proteasome system operate at the molecular level.
  • PINK1/Parkin‐dependent and PINK1/Parkin‐independent pathways regulate mitophagy in mammals.
  • Receptors localised in mitochondrial membranes play a role in mitophagy.

Keywords: mitochondrial quality control; mitophagy; PINK1/Parkin; mitochondrial receptors; proteasome; proteases

Figure 1. Quality control of mitochondria. Mitochondrial quality control operates either at the molecular level with proteases, chaperones and the ubiquitin‐proteasome system (UPS) or at the organelle level with mitophagy, autophagy, mitochondria‐derived vesicles (MDVs) and mitochondria‐derived compartments (MDCs).
Figure 2. Mitophagy in Yeast. In yeast, when mitophagy is induced, outer mitochondrial membrane protein Atg32 is phosphorylated by Ck2 kinase. This phosphorylation regulates Atg32‐Atg11 interaction that mediates mitochondria recruitment to the PAS where these organelles are surrounded by phagophore membranes through an interaction between Atg32 and Atg8 proteins. In addition, mitochondrial proteins Uth1, Aup1, Atg33 and Whi2 have also been identified in mitophagy under specific conditions, but their functions are still unknown. In yeast, mitophagy is induced during nutrient starvation, stationary phase of growth or by the drug rapamycin when cells grow in medium with respiratory carbon source.
Figure 3. Mitophagy mechanisms. Mitophagy occurs in two ways: (a) ubiquitynated outer mitochondrial membrane proteins are recognised by adaptor proteins, able to interact with LC3 (microtubule‐associated protein 1A/1B‐light chain) inserted in phagophore membranes; (b) receptors localised in the outer or inner mitochondrial membranes are able to interact with LC3 and allow the recruitment of mitochondria inside the phagophore. AP: Autophagy machinery proteins.
Figure 4. PINK1/Parkin‐dependent mitophagy. (a) Under physiological conditions, PINK1 is imported to mitochondria and processed by inner mitochondrial protein PARL and degraded by the proteasome. (b) When mitophagy is induced, PINK1 is stabilised to the outer mitochondrial membrane and activated (1). PINK1 is able to phosphorylate both Parkin and ubiquitin at S65 position, a residue conserved in both Parkin and ubiquitin proteins (2). Then, two models are proposed, either some OMM protein substrates are already ubiquitinated, PINK1 phosphorylates their ubiquitin chains, leading to Parkin recruitment and activation or OMM proteins are not ubiquitinated and Parkin is recruited to mitochondria, activated and ubiquitinates OMM proteins. Then Parkin ubiquitinates other OMM proteins. Then, adaptors are recruited to these highly ubiquitinated mitochondrial areas following by autophagy machinery proteins (AP) (3,4). Finally, mitochondria are engulfed within the phagophore.
Figure 5. PINK1/Parkin‐independent mitophagy. LC3 proteins can interact with specific receptors located at the outer mitochondrial membrane directly. These receptors can be proteins (BNIP3, BCL2L13, FUNDC1, NIX and PHB2) or a lipid (cardiolipin).
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Vigié, Pierre, Bhatia‐Kiššová, Ingrid, and Camougrand, Nadine(Oct 2017) Mechanisms and Roles of Mitophagy. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0027587]