The various mitochondrial protein complexes are the building blocks of the electron transport chain, the complicated mechanism inside mitochondria that generates adenosine triphosphate (ATP), the chemical energy store molecule used to power cell activities. Nothing in a cell is simple, and the mitochondrial complexes do not operate neatly in isolation from one another. They drift in and out of supercomplex arrangements of multiple complexes, and it turns out that this supercomplex activity is important to mitochondrial function, and thus to the pace of aging. Researchers recently demonstrated that aging in mice can be slowed by inducing more supercomplex formation, for example. Here, find a review that covers what is known of the role of supercomplexes in aging and longevity.
One of the hallmarks of aging is mitochondrial dysfunction. Mitochondria are multifunctional organelles, a central function of which is the generation of cellular energy ATP through oxidative phosphorylation (OXPHOS). The OXPHOS system consists of five complexes I-V, with complexes I-IV forming the electron transport chain that transfers electrons from NADH and FADH2 to oxygen while generating a proton gradient across the inner mitochondrial membrane (IMM). This gradient drives ATP synthesis by complex V.
The abundance and activity of OXPHOS components likely decline during aging, such as reduced levels and activity of complex I, and a declining trend in complex III and complex IV. Consistently, animal models with OXPHOS defects exhibit shorter lifespans than wild type controls. Age-associated deterioration of mitochondrial OXPHOS is assumed to arise through multiple mechanisms, including the accumulation of mitochondrial DNA (mtDNA) mutations, which contributes to increased ROS production and the promotion of cellular damage.
Mitochondrial complexes organize into higher-order assemblies known as supercomplexes (SCs), which enable to efficient energy or ATP production with repressed reactive oxygen species (ROS) generation. Notably, the assembly and stability of these SCs likely decline in aged mammals. In addition, factors such as COX7RP/SCAF1 and mitochondrial lipid cardiolipin have emerged as key regulators of SC assembly. In this review, we summarize the molecular assembly, physiological roles, and longevity implications of SC in healthy mammals. We further discuss emerging evidence supporting SC modulation as a potential strategy for promoting healthy aging.
Link: https://doi.org/10.3389/fragi.2026.1876149
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