Oxidative stress and mitochondria dysfunction are inextricably linked in the onset and pathology of human diseases including neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, and Huntington's disease. Currently, the underlying molecular mechanisms that define the relationship between oxidative stress and mitochondria dysfunction in these diseases remain poorly defined. Mitochondria inner membrane (IM) proteases such as YME1L and OMA1 coordinate to regulate many aspects of mitochondrial function including energy metabolism, organellar morphology and apoptotic signaling. Imbalances in the activity of these proteases induced by genetic or environmental factors disrupt mitochondria function and predispose individuals to etiologically diverse human diseases including many neurodegenerative disorders. Despite the importance of these proteases for mitochondria function, how the activity of IM proteases is impacted by pathologic insults are poorly understood. We hypothesize that stress-induced alterations in mitochondria IM proteases directly influence mitochondrial function and dictate cell survival in response to pathologic insults. Consistent with this prediction, we have identified YME1L and OMA1 as stress-sensitive mitochondrial proteases that undergo reciprocal regulation in response to oxidative and pathologic insults. OMA1, but not YME1L, is degraded in response to cellular insults that depolarize the mitochondria membrane through a mechanism involving YME1L. In contrast, YME1L, but not OMA1, is degraded in response to cellular insults that depolarize the mitochondria membrane and induce metabolic crisis by reducing cellular ATP through a mechanism involving activated OMA1. In this proposal, we will define the impact of YME1L or OMA1 degradation on mitochondria functions including regulation of mitochondrial morphology, inner membrane proteostasis maintenance, electron transport chain activity and neuronal sensitivity to oxidative and proteotoxic insults associated with neurodegenerative disease pathology. Through these efforts, we will demonstrate that the differential stress-sensitivity of YME1L and OMA1 distinctly impacts IM proteolytic capacity and alters mitochondria function in response to oxidative insults. Thus, our work will reveal YME1L or OMA1 degradation as a new molecular mechanism involved in defining the relationship between oxidative stress, mitochondria dysfunction and cell death associated with diseases such as the neurodegenerative disorders. Additionally, our work will identify YME1L and OMA1 activity as new therapeutic targets that can be modulated to attenuate pathologic mitochondria dysfunction associated with human disease.

Public Health Relevance

Mitochondrial inner membrane proteases are critical regulators of mitochondrial morphology and function. Here, we identify stress-induced alterations in mitochondrial inner membrane protease activity that disrupts mitochondrial morphology, leads to imbalances in mitochondrial function and sensitizes cells to pathologic insults. This discovery reveals alterations in mitochondria inner membrane proteolytic activity as a previously- unanticipated contributing factor involved in the pathologic mitochondrial dysfunction associated with diverse human diseases including neurodegenerative disorders, cardiovascular disease and cancer.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS095892-03
Application #
9452139
Study Section
Neural Oxidative Metabolism and Death Study Section (NOMD)
Program Officer
Corriveau, Roderick A
Project Start
2016-04-01
Project End
2021-03-31
Budget Start
2018-04-01
Budget End
2019-03-31
Support Year
3
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
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Lebeau, Justine; Saunders, Jaclyn M; Moraes, Vivian W R et al. (2018) The PERK Arm of the Unfolded Protein Response Regulates Mitochondrial Morphology during Acute Endoplasmic Reticulum Stress. Cell Rep 22:2827-2836
Puchades, Cristina; Rampello, Anthony J; Shin, Mia et al. (2017) Structure of the mitochondrial inner membrane AAA+ protease YME1 gives insight into substrate processing. Science 358: