# Fasting Enhances Cardiomyocyte Hypoxia Tolerance by Regulating Ca2+ Transport at Mitochondria–Endoplasmic Reticulum Contact Sites

## TL;DR

Fasting improves heart cell survival in low oxygen by boosting calcium transfer between mitochondria and the endoplasmic reticulum.

## Contribution

The study reveals a new mechanism of hypoxia tolerance via MERCs and MFN2 upregulation through intermittent fasting.

## Key findings

- 16:8 circadian intermittent fasting enhances mitochondrial fusion and MERC stability.
- MFN2 upregulation improves Ca2+ transfer and mitochondrial OXPHOS activity.
- Enhanced Ca2+ transport increases ATP production and hypoxia tolerance in cardiomyocytes.

## Abstract

Mitochondria–endoplasmic reticulum contacts (MERCs) are physical structures formed between mitochondria and the endoplasmic reticulum (ER) through various tethering proteins, playing crucial roles in multiple physiological processes, including Ca2+ and lipid exchange between the ER and mitochondria, regulation of mitochondrial morphology and dynamics (fusion and fission), as well as the induction of autophagy and apoptosis. Mitofusin 2 (MFN2), a key mitochondrial fusion protein, has been identified as an essential structural component of MERCs. Our research demonstrates that 16:8 circadian intermittent fasting (CIF) leads to enhanced mitochondrial fusion. The upregulation of MFN2 reinforces MERC stability, thereby facilitating efficient Ca2+ transfer between the ER and mitochondria. This process sustains the activity of mitochondrial oxidative phosphorylation (OXPHOS) enzymes, elevates mitochondrial oxygen utilization efficiency, and ultimately augments ATP production. Consequently, these adaptations enhance cardiomyocyte tolerance to hypoxic conditions. This study elucidates a novel mechanism by which MERCs regulate cellular hypoxia resistance and proposes a potential therapeutic strategy for improving acute hypoxia tolerance through the modulation of Ca2+ transport at MERCs.