Calcium sensing and mitochondrial homeostasis

Calcium homeostasis is essential for cellular signaling and mitochondrial metabolic regulation, which are critical for meeting the metabolic demands of various cell types. Calcium modulates cellular functions by binding to calcium-sensing domains on numerous proteins. Many calcium sensors have multiple calcium binding domains with varying affinities, allowing for diverse and graded signaling. Calcium concentrations vary across cellular compartments, and the localization of calcium sensors facilitates subcellular and organelle-specific signaling. Mitochondrial calcium flux is necessary for cell viability, especially in cells with high energy needs. Dysregulated mitochondrial calcium leads to mitochondrial dysfunction, including ATP depletion, reactive oxygen species production, loss of mitochondrial membrane potential, mitochondrial permeability transition pore opening, and apoptogen release. These disruptions cause metabolic stress, triggering cell death and contributing to pathological conditions. Mitochondrial-induced cell death plays a key role in degenerative diseases and other cell death-related disorders. Understanding the molecular mechanisms behind mitochondrial stress responses may identify new therapeutic targets for conditions linked to mitochondrial dysfunction. Recent studies have shown that mitochondrial calcium uptake protein 1 (MICU1), located in the intermembrane space, regulates the cristae structure through the mitochondrial contact site and cristae organizing system (MICOS) independently of its established role in controlling mitochondrial calcium uniporter (mtCU) channel opening. This finding suggests that calcium sensors may have additional molecular functions beyond mitochondrial calcium uptake. MICU proteins, including MICU1, MICU2, and MICU3, regulate mtCU activity by controlling its open probability in response to calcium. This regulation depends on calcium binding to EF-hand domains, with mtCU remaining closed until cytosolic calcium levels reach a threshold. Knockout models for MICU proteins show abnormalities in mitochondrial ultrastructure not observed in mtCU-specific knockout models, suggesting that MICUs regulate other mitochondrial processes. The current research hypothesis is that MICU proteins influence mitochondrial processes beyond mitochondrial calcium uptake. Over the next five year, our research program will focus on three key questions: 1) do MICU proteins universally affect MICOS and mitochondrial ultrastructure? 2) what is the cell type-specific regulatory role of MICU proteins in mitochondrial ultrastructure? 3) do MICU proteins collaborate in regulating calcium sensing at mtCU and MICOS? By employing genetic, molecular, imaging, and protein biochemistry approaches in cellular and mouse models, this investigation aims to clarify the molecular mechanisms involved in mitochondrial calcium sensing and its effects on cellular physiology. This research addresses critical gaps in understanding mitochondrial physiology, focusing on the interplay between mitochondrial calcium sensing, mitochondrial calcium flux, and mitochondrial ultrastructure. The outcomes may reveal new strategies for treating diseases related to mitochondrial dysfunction. Project Number: 1R35GM160213-01 | Fiscal Year: 2025 | NIH Institute/Center: National Institute of General Medical Sciences (NIGMS) | Principal Investigator: Dhanendra Tomar | Institution: WAKE FOREST UNIVERSITY HEALTH SCIENCES, WINSTON-SALEM, NC | Award Amount: $387,500 | Activity Code: R35 | Study Section: Maximizing Investigators' Research Award - D Study Section[MRAD] View on NIH RePORTER: https://reporter.nih.gov/project-details/11201310