Quality control of mitochondria: protection against neurodegeneration and ageing

Abstract

Dysfunction of mitochondria has severe cellular consequences and is linked to ageing and neurodegeneration in human. Several surveillance strategies have evolved that limit mitochondrial damage and ensure cellular integrity. Intraorganellar proteases conduct protein quality control and exert regulatory functions, membrane fusion and fission allow mitochondrial content mixing within a cell, and the autophagic degradation of severely damaged mitochondria protects against apoptosis. Here, we will summarize the current knowledge on these surveillance strategies and their role in human disease.

Figure 1

Quality control (QC) surveillance of mitochondria. Intraorganellar proteases exert QC and regulatory functions to maintain respiratory chain (RC) activity. The functionality of damaged mitochondria can be restored by fusion and content mixing within the mitochondrial network. Severely damaged mitochondria fragment and are removed by mitophagy or induce apoptosis by the release of pro-apoptotic proteins.

Figure 2

Quality control (QC) of mitochondrial proteins. ATP-dependent proteases present in various subcompartments of mitochondria recognize non-native polypeptides and trigger their proteolysis to peptides that are further degraded by oligopeptidases. At the same time, energy-dependent proteases can act as processing enzymes ensuring assembly and integrity of RC. Recent evidence links the UPS to mitochondrial QC and the regulation of mitochondrial dynamics. OM, outer membrane; IMS, intermembrane space; IM, inner membrane; M, matrix.

Figure 3

Regulation of RC assembly and maintenance by proteases. (A) The assembly of mitochondrial ribosomes and synthesis of mitochondrially encoded RC subunits require maturation of newly imported MrpL32 by the m-AAA protease. (B) Biogenesis of the ROS scavenger Ccp1 in yeast mitochondria depends on ATP-dependent membrane dislocation of the precursor protein by the m-AAA protease and maturation by the rhomboid protease Pcp1.

Figure 4

Regulation of mitochondrial dynamics by proteolysis. (A) Degradation of the yeast mitofusin Fzo1 can occur along two independent pathways. Constitutive turnover is dependent on the F-box protein Mdm30. Fzo1 turnover induced by cell cycle arrest (in the presence of α-factor) is mediated by UPS but does not require Mdm30. (B) Alternative topogenesis of Mgm1. Proteolytic conversion of L-Mgm1 to S-Mgm1 by the rhomboid protease Pcp1 depends on the mitochondrial membrane potential (ΔΨ), matrix ATP, and the mitochondrial import motor (PAM). (C) Model for the processing of OPA1 in mammalian mitochondria. After processing of newly imported OPA1 by MPP, long and short isoforms of OPA1 are generated by constitutive (left pathway) and inducible (right pathway) cleavage at sites 2 and site 1, respectively. m- and i-AAA proteases and PARL have been linked to OPA1 processing, but the exact proteolytic pathways remained speculative.

Figure 5

Quality control of mitochondria by mitophagy. ROS produced by damaged mitochondria induces mitochondrial fragmentation and mitochondrial permeability transition (MPT). Damaged mitochondria are engulfed by autophagosomes selectively and eliminated, preventing the release of pro-apoptotic proteins and apoptosis.