mPOS is a novel mitochondrial trigger of cell death - implications for neurodegeneration

Abstract

In addition to its central role in energy metabolism, the mitochondrion has many other functions essential for cell survival. When stressed, the multifunctional mitochondria are expected to engender multifaceted cell stress with complex physiological consequences. Potential extra-mitochondrial proteostatic burdens imposed by inefficient protein import have been largely overlooked. Accumulating evidence suggests that a diverse range of pathogenic mitochondrial stressors, which do not directly target the core protein import machinery, can reduce cell fitness by disrupting the proteostatic network in the cytosol. The resulting stress, named mitochondrial precursor overaccumulation stress (mPOS), is characterized by the toxic accumulation of unimported mitochondrial proteins in the cytosol. Here, we review our current understanding of how mitochondrial dysfunction can impact the cytosolic proteome and proteostatic signaling. We also discuss the intriguing possibility that the mPOS model may help untangle the cause-effect relationship between mitochondrial dysfunction and cytosolic protein aggregation, which are probably the two most prominent molecular hallmarks of neurodegenerative disease.

Keywords: mitochondria; mitochondrial precursor overaccumulation stress; neurodegeneration.

Fig. 1. Mitochondrial Precursor Over-accumulation Stress (mPOS) and its relationship to UPRam, UPR^mt and ISR

In unstressed cells, mitochondrial protein import is efficient and precursor proteins in the cytosol are kept to a minimum. Protein import can be reduced by intra- and extra-mitochondrial stressors (listed in Fig. 2) to cause mPOS. Unimported mitochondrial proteins can then activate the unfolded protein response activated by mistargeting of proteins (UPRam), which includes upregulation of proteasome activity. mPOS also activates the integrated stress response, characterized by the phosphorylation of eIF2α. This increases the translation of select transcriptional factors including ATF4 that in turn upregulates stress response genes. OXPHOS defect, mtDNA depletion and defective mitochondrial protein quality control (PQC) can cause mitochondrial proteotoxic stress. This triggers the mitochondrial unfolded protein response (UPR^mt), driven by failure to import of ATFS-1 in worms and ATF5 in humans into mitochondria. ATFS-1/ATF5 translocates to the nucleus and drives transcription of mitochondria-destined stress response genes such as HSP60, mtDNAJ, and ClpP.

Fig. 2. Schematic of pathways inducing mPOS

(1) Mutations in the core mitochondrial protein import machinery (TIM, translocase of the inner membrane; TOM, translocase of the outer membrane). (2) IMM protein misfolding. (3) Reduced IMM protein quality control, which can be caused by mutant IMM proteases. (4) mtDNA mutations, which disrupts the respiratory chain to reduce Δψ_m and increases protein misfolding through imbalanced mitochondrially and nuclear-encoded respiratory complex subunits. (5) Δψ_m dissipation by factors such as reduced respiration and increased proton leak. (6) Defects in precursor delivery to the OMM including mutations in the mitochondrial targeting sequences. (7) Defects in stabilizing (e.g., by mutant ubiquilin (UBL) or heat shock protein 70 kDa (HSP70)), or degrading (e.g., reduced proteasome function) unimported proteins. (8) Increased protein burden in the cytosol. OMM, outer mitochondrial membrane; IMS, intermembrane space; IMM, inner mitochondrial membrane.

Fig. 3. Models by which mPOS may reconcile mitochondrial dysfunction and cytosolic protein aggregation in neurodegeneration

(A) Model 1, cytosolic aggregates precede mitochondrial damage and mPOS during ageing. (B) Model 2, unimported proteins induced by mPOS provide a seeding structure with which cytosolic proteins co-aggregate during ageing. Blue, mitochondrial precursor proteins; red, cytosol-derived protein aggregates; orange, ribosomes.