Determining the role of the mitochondrial permeability transition pore on aging - PROJECT SUMMARY Mitochondrial dysfunction is a hallmark of aging and age-related diseases, including heart attack, stroke, and neurodegenerative disorders. Severe mitochondrial dysfunction often results from the opening of the mitochondrial permeability transition pore (mPTP), a pathological channel in the inner mitochondrial membrane triggered by excessive cytosolic Ca2⁺ and high reactive oxygen species (ROS) levels. During conditions such as ischemia/reperfusion (I/R) injury, mitochondria import Ca2⁺ into the matrix to buffer cytosolic levels. This accumulation can cause mitochondrial swelling and mPTP opening, allowing Ca2⁺ release back into the cytosol. Prolonged mPTP activation leads to outer membrane rupture, further Ca2⁺ release, and ultimately, cell death. While extensively studied in I/R-related diseases, the role of the mPTP in normal aging remains poorly understood. To address this knowledge gap, we developed a Caenorhabditis elegans model to study mPTP function in aging. Our findings reveal that mPTP activation accelerates aging, while its inhibition extends lifespan, demonstrating its direct role in longevity regulation (Angeli et al., 2021, eLife). With its short lifespan, genetic tractability, and conserved mitochondrial processes, C. elegans offers a powerful model for uncovering how the mPTP influences aging. The cellular Ca2⁺ signaling pathways that regulate mPTP opening remain largely unknown. Our preliminary data suggest that Ca2⁺ released from the endoplasmic reticulum (ER)—the largest intracellular Ca2⁺ reservoir—activates calmodulin, a key mediator of Ca2⁺-dependent signaling, possibly via interactions with kinases, phosphatases, and other calmodulin-binding proteins (CBPs). We hypothesize that an ER-to-cytoplasm Ca2⁺ signaling cascade triggers mPTP activation, driving organismal aging. Aim 1 will determine whether ITR-1, the ER receptor responsible for Ca2⁺ release, along with calmodulin (CMD-1) and CBPs, are required for mPTP activation and mPTP-dependent aging. Additionally, we will leverage the advantages of C. elegans to identify specific tissues with a predominant influence on this process. Our preliminary findings indicate robust mPTP activation in the intestines, which serve multiple functions beyond digestion, including detoxification, immunity, and fat metabolism. Aim 2 will assess whether intestinal mPTP activation is sufficient to drive organismal aging. These studies will provide novel insights into the role of the mPTP in aging, with broad implications for human health.
