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.

Visualization of Sirtuin 4 Distribution between Mitochondria and the Nucleus, Based on Bimolecular Fluorescence Self-Complementation

“…In addition to Sirt4, Sirt3 and Sirt5 are also known to harbor an N-terminal MTS [10,80,81], a peptide with positively charged amino acids, essential for importation into the mitochondrial matrix [82]. However, the importation of proteins into mitochondria can stagnate under certain stress conditions, which consequently leads to an abundance of these proteins outside of the organelle [83,84]. If these proteins are not instantly degraded, they can initiate signaling pathways to further promote or counteract cellular stress [85].…”

The mitochondrial surface receptor Tom70 protects the cytosol against mitoprotein-induced stress

“…The rather abundant, hydrophobic and aggregation-prone Pet9 protein is particularly problematic here. Previous studies already identified Pet9 as well as its human homolog ANT as proteins with high cytotoxic potential (Coyne and Chen, 2018;Hoshino et al, 2019;Liu et al, 2019;Wang and Chen, 2015;Wang et al, 2008). Mutations that even further increased their aggregation propensity are the cause of Autosomal Dominant Progressive External Ophthalmoplegia 2 in humans (Kaukonen et al, 2000) and trigger mitochondrial precursor over-accumulation stress (mPOS) in yeast (Wang and Chen, 2015).…”

The special considerations of gene therapy for mitochondrial diseases

“…Production of defective and/or misfolded mitochondrial proteins encoded from the nuclear genome can lead to a toxic buildup of mitochondrial protein precursors in the cytosol (a process referred to as mitochondrial precursor overaccumulation stress, or mPOS), as well as dysfunction within the mitochondria itself (including disrupted OXPHOS, proteotoxic stress, and mtDNA depletion) due to the accumulation of misfolded proteins. 42 More importantly, there are even indications that overexpression of an otherwise wild type, nuclear-encoded mitochondrial protein can trigger mPOS in human cells through over-crowding. 43 If true, this would represent a major challenge to the use of gene therapy to replace defective mitochondrial proteins encoded from either genome, as high expression levels are generally required to produce any significant improvements in a patient's condition.…”