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Elucidation of the Genuine Impact of Calcium Overload on Mitochondria

Award Number: R01HL183792
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/15/2026
PERIOD OF PERFORMANCE END DATE: 04/30/2030

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Elucidation of the Genuine Impact of Calcium Overload on Mitochondria - Project Summary Mitochondria are the primary source of energy for most mammalian cells, but they are at an extreme risk of calcium toxicity due to their nature. Under normal physiological conditions, cytosolic and mitochondrial calcium levels are highly regulated by fine-tuned control mechanisms to maintain nanomolar to micromolar concentrations despite millimolar concentrations outside the cell. When these control mechanisms fail, mitochondrial calcium levels soar into overload and causes membrane disruption, energetic failure, and cell death. This puts them at the center of many diseases and pathologies, particularly ischemia/reperfusion injury. While recent advances in molecular biology have led to the identification and characterization of the molecular pathways for calcium uptake and extrusion, there still is very little known about how mitochondria store calcium and how this regulates energy metabolism. A significant barrier to the study of mitochondrial calcium storage is the limited ability to quantify and image this system. Based on prior work and preliminary data, a novel hypothesis emerges which postulates that mitochondrial calcium sequestration regulates energy metabolism through calcium phosphate formation and cristae remodeling. Specific Aims: (1) elucidate the ultrastructural changes during mitochondrial permeability transition, (2) explain how calcium phosphate granules modulate the mitochondrial structure/function axis, and (3) investigate genetic aspects and pathophysiology implications of mitochondrial ultrastructure. Approach: In this project, cryo-electron microscopy and computational physiology will be leveraged to explain how calcium overload impairs oxidative metabolism. The hypothesis will be tested at multiple spatiotemporal scales while utilizing recent advances in cryo-electron microscopy to directly visualize the ultrastructural changes associated with calcium overload. The computational approach will use a concrete theoretical framework to model, analyze, and interrogate molecular mechanisms of calcium storage and link calcium overload to changes in mitochondrial function and ultrastructure. In summary, these studies will facilitate a rational and mechanistic approach to identify new therapeutic targets and develop novel therapies to correct or prevent mitochondrial dysfunction under pathological conditions that lead to tissue injury.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $466,362 )
2026	2026	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD	EAST LANSING	MI	48824	INGHAM	USA	Cardiovascular Diseases Research	000	1	8/3/2026	NEW	$466,362
														Subtotal = $466,362

Grand Total All Awards = $466,362

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Elucidation of the Genuine Impact of Calcium Overload on Mitochondria

Award Number: R01HL183792

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 08/15/2026

PERIOD OF PERFORMANCE END DATE: 04/30/2030

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