Reply to Quistorff and Grunnet: Dysfunctional mitochondria, brain lactate, and lactate dehydrogenase isoforms

Abstract

Quistorff and Grunnet (1), on theoretical grounds, question our suggested explanation of the pathologically increased lactate levels that we reported in prematurely aging mtDNA mutator and normally aging mice (2). A clarification of the chain of events based on our experimental data is, therefore, warranted. The primary cause of lactate pathology in mtDNA mutator mice is precisely known: a mutation drastically decreasing the proofreading function of the catalytic subunit of Polγ. This leads to progressive increase of mtDNA mutation frequency in mitochondria of all cells and premature-aging phenotypes (3). Accumulating mtDNA mutations causes respiratory chain dysfunction, shown by cytochrome c oxidase (COX)/succinate dehydrogenase (SDH) staining (2). This, in turn, causes impaired pyruvate oxidation (3), and increased pyruvate levels would be expected. We have preliminary data to show such increase (measured in blood). Pyruvate to lactate conversion regenerates β-nicotinamide adenine dinucleotide (NAD+), which is essential for glycolysis (2).