Supercomplexes of the mitochondrial electron transport chain decline in the aging rat heart

Abstract

Accumulation of mitochondrial electron transport chain (ETC) defects is a recognized hallmark of the age-associated decline in cardiac bioenergetics; however, the molecular events involved are only poorly understood. In the present work, we hypothesized that age-related ETC deterioration stemmed partly from disassociation of large solid-state macromolecular assemblies termed "supercomplexes". Mitochondrial proteins from young and old rat hearts were separated by Blue Native-PAGE, protein bands analyzed by LC-MALDI-MS/MS, and protein levels quantified by densitometry. Results showed that supercomplexes comprised of various stoichiometries of complexes I, III and IV were observed, and declined significantly (p < 0.05, n = 4) with age. Supercomplexes displaying the highest molecular masses were the most severely affected. Considering that certain diseases (e.g. Barth Syndrome) display similar supercomplex destabilization as our results for aging, the deterioration in ETC supercomplexes may be an important underlying factor for both impaired mitochondrial function and loss of cardiac bioenergetics with age.

Cardiac cytochrome c and cardiolipin depletion during anthracycline-induced chronic depression of mitochondrial function

“…Alternatively, the present data could also be analyzed in the light of the aging theory and through comparison to a previous report where it was demonstrated that the failing heart in aging results from the loss of respiratory supercomplexes (Gomez et al, 2009). Gómez et al suggested that destabilization of inter-fibrillar mitochondrial string supercomplexes is the responsible for the decline in mitochondrial function during aging (Gomez et al, 2009).…”

“…Gómez et al suggested that destabilization of inter-fibrillar mitochondrial string supercomplexes is the responsible for the decline in mitochondrial function during aging (Gomez et al, 2009). Moreover, the authors pointed the possible role of Complex IV in the underlying mechanism as it is the only respiratory complex present in all supercomplexes.…”

“…associated with destabilization of supercomplexes (Gomez et al, 2009). Since DOX treatment decreased cardiolipin content in heart mitochondria, a crucial component in the biogenesis and stabilization of supercomplexes as well as for the activity of Complex IV, it may be rationale to consider that another possible mechanism is alteration of the stability of mitochondrial supercomplexes.…”

Questioning the functional relevance of mitochondrial supercomplexes by time-resolved analysis of the respiratory chain

“…Supercomplexes have been found in a wide variety of organisms ranging from bacteria and unicellular eukaryotes to multicellular organisms including fungi, higher plants, and mammals (11). In addition, the abundance and/or stability of these supramolecular edifices have been shown to respond to physiological changes (13,14), thus pointing to their physiological relevance. Yet, to our knowledge, functional data supporting these views are scarce.…”

“…This culminated in the isolation by Acin-Pérez, et al of a functional "respirasome" from mammal cells, transferring electrons all the way from NADH or succinate to molecular oxygen (12). In addition, the composition and abundance of the biochemically characterized supercomplexes have been shown to vary with growth or physiological conditions (13,14), supporting their physiological significance. However, parallel studies on whole cells aimed at understanding the dynamics of the supercomplexes and their functional relevance are lacking.…”