# Molecular mechanisms of mitochondrial metabolic regulation

> **NIH NIH F30** · STANFORD UNIVERSITY · 2024 · $41,856

## Abstract

Project Summary
Heart failure, a prominent global health issue, continues to steadily rise in incidence yet has no cure. This
condition is distinguished by the heart’s reduced ability to pump blood, largely driven by cardiac bioenergetic
abnormalities. As cardiomyocytes rely on mitochondria for 95% of their energy supply, mitochondrial dysfunction
characteristically underlies these energetic defects. NAD+ sits at the core of mitochondrial energetics, driving the
progression of the tricarboxylic acid cycle in aerobic respiration. Cardiomyocyte failure is linked to NAD+ depletion
in the mitochondrial matrix, impairing energy synthesis and sensitizing cells to death. Restoration of
mitochondrial function through NAD+ repletion is a powerful therapeutic strategy that has shown early promise
in reversing heart failure phenotypes. However, despite the pivotal role of NAD+ in mitochondrial function, a
limited understanding exists of the mechanisms governing NAD+ entry into and regulation within the
mitochondrial matrix. Notably, recent landmark studies have demonstrated that the mitochondrial matrix cannot
independently synthesize NAD+ and have identified the essential transporter responsible for matrix NAD+ import.
Yet, little is known about the molecular mechanism of this critical transport process. This project proposes to
address this gap in knowledge by exploring the molecular basis of mitochondrial NAD+ import, which will
elucidate how mitochondria maintain adequate NAD+ levels and how this process may become dysregulated in
disease. Multidisciplinary approaches will be used to investigate fundamental unknowns about the transport
mechanism, including the biochemical basis of substrate selectivity and coupling, the key protein features
governing transport activity, and the architectural determinants of substrate binding and translocation. Together,
this work will shed light on fundamental mechanisms of mitochondrial metabolic regulation and may provide a
molecular blueprint for countering mitochondrial dysfunction in the long-term treatment of heart failure.

## Key facts

- **NIH application ID:** 10901736
- **Project number:** 1F30HL174099-01
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Aswini Ram Krishnan
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $41,856
- **Award type:** 1
- **Project period:** 2024-09-16 → 2028-09-15

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10901736

## Citation

> US National Institutes of Health, RePORTER application 10901736, Molecular mechanisms of mitochondrial metabolic regulation (1F30HL174099-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10901736. Licensed CC0.

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