# Mitochondrial Turnover in the Human Heart

> **NIH NIH R01** · CEDARS-SINAI MEDICAL CENTER · 2020 · $525,000

## Abstract

Project Abstract
Heart disease is a major cause of morbidity and mortality, much of it due to ischemic injury. Mitophagy and
biogenesis (mitochondrial turnover) are essential for ischemia tolerance and appropriate recovery during
reperfusion. Factors that affect mitochondrial turnover include age, sex, time of day, comorbid conditions such
as age and metabolic syndrome, nutritional status, exercise, and a long list of drugs and natural products. The
overarching hypothesis is that monitoring mitochondrial turnover will allow us to infer a patient’s response to
ischemic stress, and that normalizing turnover will improve outcome. In this proposal we develop tools to
measure mitochondrial turnover (Aim I), define the regulation of mitochondrial turnover (Aim II), and leverage
the knowledge gained to monitor mitochondrial turnover in the human heart during cardiopulmonary bypass
(Aim III). Additionally we will measure mitochondrial function in endomyocardial biopsies of heart transplant
patients, where it will be possible to relate mitochondrial function to cardiac contractility. In Aim I we will use
our novel MitoTimer mice and organelle flow cytometry to develop a proteomic signature of mitophagy and
biogenesis. The protein profiles will be used to create a mass spectrometry assay (multiple reaction
monitoring, MRM) to infer mitochondrial turnover in tissue extracts including human heart biopsies. This index
of mitophagy and biogenesis will be used to assess mitochondrial turnover in rodents in Aim I and in human
heart biopsies in Aim III. In Aim II, we will delineate the regulation of mitophagy by PINK1, Parkin, and
optineurin; and the regulation of mitochondrial biogenesis by PGC-1alpha, PARIS, and translational machinery.
We have established polysome profiling to interrogate translational control of mitochondrial biogenesis. In Aim
III we will use paired atrial biopsies (before and after cardiopulmonary bypass) to characterize mitophagy and
biogenesis in the human heart’s response to ischemic stress; we will use paired atrial and ventricular biopsies
to gain much-needed information about the differences in mitochondrial function and cardiac proteome; and we
will correlate mitochondrial respirometry, mtDNA damage, and MRM assays of mitochondrial turnover to
correlate with clinical parameters, specifically postoperative atrial fibrillation. These studies will establish the
molecular signatures of appropriate mitochondrial turnover during cardiac surgery, providing markers of target
engagement that will position us to evaluate therapeutic interventions. Importantly, understanding this pathway
will reveal new therapeutic targets that regulate mitochondrial turnover and influence function of the human
heart recovering from ischemia.

## Key facts

- **NIH application ID:** 9852461
- **Project number:** 5R01HL132075-04
- **Recipient organization:** CEDARS-SINAI MEDICAL CENTER
- **Principal Investigator:** Roberta A. Gottlieb
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $525,000
- **Award type:** 5
- **Project period:** 2016-12-15 → 2020-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9852461

## Citation

> US National Institutes of Health, RePORTER application 9852461, Mitochondrial Turnover in the Human Heart (5R01HL132075-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9852461. Licensed CC0.

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