# Integrative Proteomic and Bioenergetic Profiling Reveals Diet- and Strain-Specific Mitochondrial Dysfunction in Cohen Diabetic Rat Hearts

## TL;DR

This study shows how diet and genetics together affect heart mitochondria in diabetic rats, leading to heart disease.

## Contribution

The study reveals diet- and strain-specific mitochondrial changes in diabetic rat hearts using proteomic and bioenergetic profiling.

## Key findings

- Cytochrome c oxidase subunits are downregulated in diabetic rat hearts.
- Mitochondrial respiration and ATP levels are impaired in sensitive strain rats.
- Diet-specific tyrosine phosphorylation of CcO subunit I indicates inflammation-driven inhibition.

## Abstract

Mitochondrial dysfunction contributes to diabetic cardiomyopathy, yet how genetic predisposition and diet interact to reshape cardiac metabolism in diabetic and prediabetic states remains unclear. The Cohen diabetic rat model, comprising diabetes-resistant (CDr) and diabetes-sensitive (CDs) strains, provides a unique platform to dissect this interplay. Here, we present an integrative global proteomic and bioenergetic characterization of cardiac tissue from CDr and CDs rats fed either a regular or a diabetogenic diet. Proteomic pathway mapping revealed downregulation of cytochrome c oxidase (CcO) subunits, strain-dependent rewiring of fatty-acid oxidation pathways, and CcO subunits switch from “heart-type” to “liver-type” isoforms in the sensitive strain. These changes were accompanied by impaired mitochondrial respiration, ATP depletion, and disruption of mitochondrial quality-control mechanisms, together with increased accumulation of tyrosine 304 phosphorylation of cytochrome c oxidase subunit I, indicative of inflammation-driven regulatory inhibition in a diet-specific manner. These findings establish an understanding of how genetic susceptibility and diet contribute to cardiac mitochondrial dysfunction in the Cohen diabetic rat model.