# Disruption of ATP Synthase Spatiotemporal Organization, Ca2+ Dynamics, and Contractile Function in Senescent Cardiomyocytes

## TL;DR

This study shows that aging heart cells have reduced energy production due to disrupted ATP synthase organization, leading to calcium imbalances and poor heart function.

## Contribution

The study reveals novel insights into how ATP synthase dysfunction in aging cardiomyocytes contributes to heart failure through disrupted energy and calcium dynamics.

## Key findings

- Senescent cardiomyocytes show increased ATP synthase mobility and cristae fenestrations, linked to reduced ATP production.
- Disrupted ATP metabolism correlates with dysregulated calcium dynamics and irregular heartbeats in aging cells.
- Enhanced ATP hydrolysis and mitochondrial instability contribute to energy deficits in senescent cardiomyocytes.

## Abstract

Heart disease is the leading cause of death in the elderly population. Age‐related heart failure is frequently associated with energy deficits in cardiomyocytes. These cells rely on their abundant, cristae‐rich mitochondria for ATP production. ATP synthase, localized along the cristae rims, is central to this process. It is presumed that its function is tightly bound to its spatial organization, but details remain unclear. Here, we explored the spatiotemporal organization of ATP synthase in senescent human iPSC‐derived CM in conjunction with its functions. We found changes in the stoichiometry of F1 and FO subunits in senescent CM. The ratio of FO‐SU c to F1‐SU β increased. The oligomeric organization of the complex was weakened. Using single‐molecule localization and tracking microscopy, we observed an increased enzyme mobility within cristae that displayed increased fenestrations. This coincided with decreased mitochondrial ATP level, increased ATP hydrolysis capacity, and a moderate increase in mitochondrial transition pore opening. Disturbed ATP production was correlated with dysregulated calcium dynamics, characterized by heightened spikes and slower cytosolic clearance. Consequently, senescent cardiomyocytes exhibited irregular autonomous and paced beating patterns. These findings indicate that, in senescent cardiomyocytes, functional decline is closely linked to disrupted ATP metabolism, driven by the aberrant organization, dynamics, and activity of ATP synthase within remodeled cristae.

Enhanced ATP hydrolysis, ΔΨm flickering, and destabilized ATP synthase dimers collectively reduce ATP availability in senescent cardiomyocytes. This energy deficit is associated with disrupted Ca2⁺ dynamics and contractility.