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Molecular mechanisms of mitochondrial complex I rescue by hypoxia and genetic suppressors

Award Number: R21NS151350
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2026
PERIOD OF PERFORMANCE END DATE: 08/31/2028

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Molecular mechanisms of mitochondrial complex I rescue by hypoxia and genetic suppressors - Project Summary Mitochondrial complex I (CI) dysfunction underlies devastating pediatric disorders such as Leigh Syndrome and contributes to age-associated neurodegeneration, including Parkinson’s and Alzheimer’s disease. Surprisingly, environmental hypoxia rescues C. elegans and mouse CI mutants, even reversing neurodegeneration in a mouse model of Leigh syndrome. Recent genetic screens in C. elegans identified “hypoxia-mimetic” mutations in CI subunits that restore electron flow, however due to a lack of structural data the molecular mechanisms by which hypoxia and these mutations rescue CI function remain unknown. We hypothesize that hypoxia and hypoxia-mimetic mutations stabilize specific conformations or assembly states of CI supercomplexes (SCs) that reduce pathological reverse electron transfer (RET) and restore forward electron flow. We will test this hypothesis by combining C. elegans genetics and mitochondrial biochemistry with state-of-the-art cryogenic electron microscopy (cryoEM) to define the structural basis of hypoxia rescue. This work will solve the first structures of C. elegans respiratory supercomplexes; wild-type structures alone will provide insights into longstanding mitochondrial mutant phenotypes such as volatile anesthetics sensitivity, neurodegeneration, and longevity. By then comparing wild type with CI reduction-of-function mutants, CI “hypoxia-mimetic” mutants, and CI “hypoxia-resistant” mutants, we will uncover the structural basis for CI mutant rescue. in vitro ETC activity assays performed on mitochondrial membranes will then be used to functionally validate our hypotheses. Combining the Meisel lab’s expertise in C. elegans genetics and bioenergetics with the Letts lab’s expertise in ETC SC structural biology, the work proposed in this R21 will establish a hypothesis-generation/hypothesis-testing pipeline that will set the standard for elucidating mitochondrial respiratory physiology and pathophysiology, with important implications for translating hypoxia into a viable therapy for neurodegenerative diseases.


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 = $436,864 )
2026	2026	BRANDEIS UNIVERSITY	415 SOUTH ST	WALTHAM	MA	02453	MIDDLESEX	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	8/20/2026	NEW	$436,864
														Subtotal = $436,864

Grand Total All Awards = $436,864

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Molecular mechanisms of mitochondrial complex I rescue by hypoxia and genetic suppressors

Award Number: R21NS151350

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/01/2026

PERIOD OF PERFORMANCE END DATE: 08/31/2028

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