Interspecies Differences in Mitochondrial Structure and Function: Implications for Cardiovascular Physiology in Translational Research

Abstract

The heart is among the most energy-hungry organs in the body, and almost all of that energy is supplied by mitochondria. For this reason mitochondrial biology sits close to the centre of cardiovascular physiology and, increasingly, of cardiovascular drug discovery. Yet most of what we know about cardiac mitochondria has been pieced together from a handful of laboratory species – mostly mice and rats – whose mitochondria are not simply scaled-down versions of our own. This review examines how mitochondrial structure and function differ between the species that populate translational cardiovascular research, and why those differences matter when results are carried from the bench to the clinic. We consider the conserved architecture of the organelle alongside the features that vary: the lipid composition of the inner membrane and its link to metabolic rate, the magnitude of proton leak and mild uncoupling, the balance between reactive oxygen species production and antioxidant capacity, the handling of calcium, and the sensitivity of the permeability transition pore. Each of these axes tends to scale, often steeply, with body mass and life history, so that a mouse cardiomyocyte beating some six hundred times a minute operates under bioenergetic constraints quite unlike those of a resting human heart. We use the repeated failure of mitochondria-targeted cardioprotection in clinical trials, despite striking success in rodents, as a cautionary illustration. We argue that progress depends less on finding a single “best” model than on interpreting each model in light of its mitochondrial idiosyncrasies, and on combining small animals, large animals and human cell-based systems thoughtfully.

Highlights
Cardiac mitochondria share a deeply conserved architecture across vertebrates, yet differ markedly in membrane lipids, coupling efficiency and ion handling between species.
Mass-specific metabolic rate, heart rate and membrane polyunsaturation scale with body size, shaping species-specific mitochondrial bioenergetics and redox balance.
Differences in calcium handling and permeability-transition sensitivity help explain why cardioprotection that works in rodents has translated poorly to patients.
Rational model selection – and the complementary use of large animals and human iPSC-derived cardiomyocytes – is essential for credible translation.