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Understanding the Changes in Mitochondrial Morphology through Dynamic and Three-dimensional Fluorescence Micrographs
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Multiscale mitochondrial cristae remodeling links Opa1 downregulation to reduced OXPHOS capacity in aged hearts

Isidora Molina-Riquelme1, Gonzalo Barrientos1, Leonhard Breitsprecher2

  • 1Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago de Chile 8331150, Chile.

Proceedings of the National Academy of Sciences of the United States of America
|December 30, 2025
PubMed

Insights

Cardiac aging is linked to mitochondrial dysfunction. This study reveals that changes in mitochondrial cristae structure, not protein levels, impair heart function, serving as an early aging signal.

Area of Science:

  • Cardiovascular Biology
  • Mitochondrial Biology
  • Aging Research

Background:

  • Cardiovascular diseases are a leading cause of death, strongly linked to aging.
  • Mitochondrial dysfunction is a key feature of cardiovascular aging.
  • Heart ATP production relies on oxidative phosphorylation (OXPHOS) within mitochondrial cristae.

Purpose of the Study:

  • To investigate age-related changes in mitochondrial cristae structure in human and mouse hearts.
  • To correlate structural cristae alterations with mitochondrial function and aging.
  • To identify early markers of cardiac aging.

Main Methods:

  • Utilized multiple-scale electron microscopy, including transmission electron microscopy (TEM) and serial block-face scanning electron microscopy (SBF-SEM).
  • Employed electron tomography to analyze cristae connectivity and fenestration.
  • Assessed Opa1 protein levels and maximal OXPHOS respiration.

Main Results:

  • Aged human and mouse hearts showed decreased cristae density and width.
  • Cristae remodeling, reduced connectivity, and increased fenestration were observed in aged mice.
  • Opa1 downregulation correlated with reduced maximal OXPHOS respiration.
  • These structural changes occurred independently of major OXPHOS protein alterations.

Conclusions:

  • Alterations in mitochondrial cristae structure alone can impair cardiac oxidative metabolism.
  • Cristae structural changes are an early indicator of cardiac aging, preceding broader mitochondrial morphology changes.
  • Targeting cristae structure may offer therapeutic strategies for age-related cardiovascular decline.

Keywords:
Opa1agingcristaeheartmitochondria

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