Impact of mitochondrial structure on cellular homeostasis and hepatic injury

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Abstract: In the cellular system, mitochondria form an intricate network of interconnected mitochondrion of different shapes and sizes. The mitochondrion forms close contact with other cellular organelles which are essential in maintaining the mitochondrial integrity as well as the functions. Emerging evidence suggests the complexity of the mitochondrial architecture and processes involved in the maintenance of functional mitochondrial pool in the cell. The mitochondrial architecture is regulated by various pathophysiological signals like nutrient availability, hormonal regulation, and stress conditions which regulates cytosolic calcium (cCa2+) dynamics as well. The dynamic changes in the cCa2+ regulate mitochondrial shape through a Ca2+-sensing mitochondrial outer membrane-anchored EF-hand containing protein Miro1. This phenomenon termed as the mitochondrial shape transition (MiST) is independent of Miro1's role in mitochondrial trafficking and Drp1-induced mitochondrial fission. Although Ca2+ signals fine-tune the mitochondrial bioenergetic output, and sustained elevation of cCa2+ drives excessive mitochondrial Ca2+ uptake which is a prerequisite for the opening of mitochondrial permeability transition pore (MPTP), mitochondrial swelling, plasma membrane rupture, and necrotic cell death. Preliminary data suggest that in response to MiST, endoplasmic reticulum (ER)-mitochondrial tethering is increased which may be essential for both MPTP opening and the mitophagic response. In response to hepatic ischemia-reperfusion injury (IRI), MPTP opening leads to the onset of hepatic necrosis and subsequent organ failure. Mitochondrial integrity is crucial for hepatic function and survival after IRI. However, the underlying molecular mechanism for the maintenance of mitochondrial integrity is largely unidentified. Therefore,we will mechanistically examinethe link betweenMiST, MPTP, and mitophagy with a particular emphasis on the role of Miro1 in MPTP formation, initiation of mitophagy, and induction of necrosis in response to the hepatic IRI. The project outline will enable the development of essential skills and expertise needed to develop PI's independent research program focusing on the mitochondrial biology in the hepatic system.