Unlocking the Mysteries of Mitochondria-induced Cellular Stress and Diseases
mitochondrial Precursor Overaccumulation Stress (mPOS)
Severe mitochondrial damage affects cell fitness and viability by energy depletion, and very often, accompanied with increased oxidative stress. However, mitochondria are multifunctional. Whether mitochondrial damage also affects cell fitness and survival by non-bioenergetic mechanisms is poorly understood. Our studies revealed that mitochondrial protein import is readily saturable inside the cell. It is affected by a variety of mitochondrial stressors (e.g., protein misfolding, mtDNA mutation and low membrane potential), even without directly disrupting the core protein import machinery. More importantly, our biochemical analysis demonstrated that the cytosol has a limited capacity to degrade unimported mitochondrial proteins. Mitochondrial damage can therefore lead to the accumulation of unimported mitochondrial proteins in the cytosol. We phenotypically and biochemically captured the cytosolic stress caused by unimported mitochondrial proteins, which we named mitochondrial Precursor Over-accumulation Stress (mPOS). The overall implication of these findings is that mitochondrial damage can directly cause proteostatic stress in the cytosol. This can induce cell death independent of bioenergetic defect. Using cell-based approaches, we are interested to determine the mechanisms by which mPOS causes cell death, and to identify molecular pathways that protect cells against mPOS.
Role of mPOS in muscle wasting, cardiac dysfunction and neurodegeneration
Mitochondrial abnormalities and cytosolic protein misfolding are probably the two most important hallmarks of aging and aging-associated degenerative disorders that include Parkinson's disease, amyotrophic lateral sclerosis, frontotemporal dementia, Alzheimer's disease and some subtypes of muscle atrophies. The mPOS hypothesis provides a conceptual framework for untangling the interaction between these two ostensibly unrelated pro-degenerative pathways. We are interested to learn whether mPOS plays a role in aging-associated muscle wasting, cardiac dysfunction and neurodegeneration, and to develop anti-mPOS interventions that can potentially be used to treat these diseases.