The plasma membrane forms the barrier between the cytoplasm and the environment. Cells constantly and selectively transport molecules across their plasma membrane without disrupting it. Any disruption in the plasma membrane compromises its selective permeability and is lethal, if not rapidly repaired. Thus, the process of plasma membrane repair is critical; however, our understanding of this fundamental process is incomplete. There is a growing understanding of the organelles, proteins, lipids, and small molecules that serve as machinery and signals for plasma membrane repair, but how these signals coordinate the movement and activity of repair machinery remains less well-understood.
Calcium is a ubiquitous regulator of plasma membrane repair. It is required to activate repair machinery and regulates downstream signaling. However, high concentrations of calcium are toxic and can cause cell death. Thus, calcium signals must be tightly regulated in space and time for efficient repair. Other factors, such as redox signaling and cellular energy balance may also play key roles in ensuring the proper movement and activity of repair machinery. Each of these factors is implicated in plasma membrane repair, and each is also a critical aspect of mitochondrial physiology. It has previously been shown that mitochondrial activity is required for plasma membrane repair in skeletal muscle myofibers; however, the mechanism for mitochondria-mediated repair is unknown. This dissertation project sought to investigate what role mitochondria play in plasma membrane repair. We found that rapid uptake of calcium by mitochondria upon injury helps to prevent cytosolic calcium overload. Mitochondria use calcium to generate localized redox signaling, which is kept close to the site of injury through selective fragmentation of injury-proximal mitochondria. Redox signaling activates the GTPase RhoA in order to mediate cytoskeletal rearrangements that facilitate repair. Thus, mitochondria utilize cellular signals generated due to plasma membrane injury in order to coordinate subcellular responses that facilitate repair.
Mitochondrial activity is often disrupted in diseases of skeletal muscle, particularly those characterized by excessive myofiber damage. In these diseases, mitochondrial dysfunction contributes to pathology due to defects such as reduced energy production, excessive generation of reactive oxygen species, altered mitophagy, or apoptosis. However, given the requirement of mitochondria in the repair of physiological plasma membrane injury, defects in the mitochondrial response to injury may also contribute to poor plasma membrane repair in skeletal muscle disease. Thus, we also investigated whether mitochondrial dysfunction contributes to pathogenesis of skeletal muscle disease through lack of mitochondria-mediated plasma membrane repair, which has not been explored. Here, we found that chronic dysfunction on a global scale, and injury-triggered imbalances in mitochondrial calcium and redox homeostasis both have the ability to inhibit plasma membrane repair. These findings help to identify aspects of mitochondrial physiology that are amenable to targeted therapies with the goal of reversing mitochondrial dysfunction in skeletal muscle diseases and subsequently improving plasma membrane repair.
Collectively, these studies shed light on a novel role for mitochondria in plasma membrane repair and describe how defects in mitochondria-mediated repair contribute to pathogenesis of skeletal muscle disease. The findings presented here add to our growing understanding of plasma membrane repair and highlight its importance in progression of human disease. First, we identify mitochondria as a signaling hub for plasma membrane repair. This fills a knowledge gap in the field by explaining how injury-triggered increase in calcium is able to facilitate downstream cellular responses required for repair. Second, we describe the importance of mitochondrial dysfunction to the progression of skeletal muscle diseases that are characterized by myofiber damage and degeneration. This highlights the critical role of plasma membrane repair defects in pathogenesis of these diseases and provides new avenues for targeted therapies.
|Advisor:||Jaiswal, Jyoti K., Colberg-Poley, Anamaris|
|Commitee:||Caldovic, Ljubica, Liu, Judy, Partridge, Terence|
|School:||The George Washington University|
|Department:||Biochemistry & Systems Biology|
|School Location:||United States -- District of Columbia|
|Source:||DAI-B 79/12(E), Dissertation Abstracts International|
|Keywords:||Dystrophy, Injury, Mitochondria, Plasma membrane repair, Reactive oxygen species, Skeletal muscle|
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