The roles of cytosolic and intramitochondrial Ca2+ and the mitochondrial Ca2+-uniporter (MCU) in the stimulation of mammalian oxidative phosphorylation [Letters to the Editor]

Szibor et al. (1) concluded that mitochondrial pyruvate oxidation is regulated primarily by cytosolic Ca2+ ([Ca2+]cyt) activation of the malate-aspartate shuttle, rather than by mitochondrial Ca2+ ([Ca2+]mit) activation of intramitochondrial dehydrogenases. Pyruvate dehydrogenase (PDH) activity largely reflects the ratio of active nonphosphorylated PDH to inactive phosphorylated PDH (PDHP) (2), but Szibor et al. (1) did not measure PDH/PDHP ratios. Moreover, their studies used unphysiological conditions with isolated mitochondria (saturating ADP); with synaptosomes, thymocytes, and fibroblasts (uncoupler and high pyruvate); and with perfused hearts (high pyruvate). These conditions likely suppress ATP-linked PDH kinase activity (inhibited by ADP and pyruvate), resulting in very high PDH/PDHP ratios. This severely limits any potential activation of PDH by the [Ca2+]mit-stimulated PDHP phosphatase, inevitably delivering the results obtained. Under more physiological conditions, where PDH/PDHP ratios are lower, many studies have shown that [Ca2+]mit is a key activator of pyruvate oxidation (3–5).We suggest that stimulation of the malate-aspartate shuttle by [Ca2+]cyt (increasing mitochondrial oxidation of cytoplasmic NADH) complements regulation of intramitochondrial dehydrogenases by [Ca2+]mit (2). The latter may be regarded as an evolutionary refinement of “intrinsic” mechanisms (also present in lower organisms) increasing ATP production without lowering ATP/ADP ratios (...
Source: Journal of Biological Chemistry - Category: Chemistry Authors: Tags: Letters to the Editor Source Type: research