A mitochondrial medley

Abstract

This month's installment of Generally Physiological focuses on mitochondria, exploring circadian regulation of mitochondrial oxidative metabolism, what happens when you eliminate the mitochondrial calcium uniporter, and Ca 2+ transport by the inner mito-chondrial membrane protein Letm1. Circadian regulation of mitochondrial bioenergetics Circadian clocks synchronize physiological processes with the day/night cycle, enabling coordination of feed-ing/fasting and activity/rest cycles with the appropriate time of day. The coenzyme nicotinamide adenine dinucleotide (NAD +), which plays a crucial role in metabolic redox reactions , participates in a feedback loop with the core clock machinery: NAD + regulates the transcription of clock genes through the NAD +-dependent deacetylase SIRT1, while expression of the rate-limiting enzyme in NAD + biosynthesis is controlled by the clock (see Rey and Reddy, 2013). Noting that NAD + regulates the mitochon-drial deacetylase SIRT3, Peek et al. (2013) explored the possibility that oscillations in NAD + could also provide a mechanism for the circadian regulation of mitochondrial oxida-tive metabolism. Liver fatty acid oxidation and NAD + abundance showed synchronized oscillations in fasted mice maintained in darkness, with peaks occurring toward the end of the rest cycle. Similarly, cultured mouse myoblasts showed rhythmic oscillations in NAD + accumulation, fatty acid oxidation, oxygen consumption, and glucose oxidation. Livers from circadian mutant mice lacking the clock gene Bmal1 showed decreased fatty acid oxidation and total and mitochondrial NAD + compared with that from wild-type mice, and isolated mitochondria from the Bmal1 / mice showed decreased oxygen consumption when supplied with fatty acids or pyruvate. Moreover, Bmal1 / fi-broblasts produced less ATP than wild-type fibroblasts under conditions favoring oxidative metabolism. Acetylation of various mitochondrial oxidative enzymes was increased in Bmal1 / mice, whereas their activity was decreased, and a mitochondrial SIRT3 target showed rhythmic oscillations in acetylation-although the abundance of SIRT3 itself remained constant. Increasing NAD + rescued deacetylation of a SIRT3 substrate, activity of medium-chain acyl dehy-drogenase (a mitochondrial enzyme that showed circadian oscillations in acetylation in wild-type mice as well as increased acetylation and decreased activity in mutants), and mito chondrial oxidative defects in circadian mutants. The authors thus conclude that circadian oscillations in NAD + regulate mitochondrial function through the SIRT3-dependent deacetylation of oxidative enzymes , to coordinate mitochondrial bioenergetics with daily rhythms in feeding and activity. Exploring the roles of mitochondrial calcium Energized mitochondria can rapidly sequester cytosolic calcium, which crosses the outer and inner mito-chondrial membranes to enter the mitochondrial matrix, traversing the latter by way of the mitochondrial calcium uniporter (MCU)-a process driven by the mitochondrial membrane potential generated by electron transport. Matrix calcium, in turn, is thought to regulate various mitochondrial functions and-when present in excess-to contribute to cell death through a mechanism involving opening of the permeability transition pore (PTP) and the consequent collapse of the mitochon-drial membrane potential. Pan et al. (2013) used a gene trap strategy to create mice lacking the MCU as a model system with which to explore MCU function and the physiological roles of matrix calcium. Although slightly smaller than wild-type mice, MCU / mice had no other gross phenotypic abnormalities. However , calcium imaging of embryonic A mitochondrial medley Circadian oscillations in NAD + abundance regulate mitochondrial oxidative metabolism by means of the deacetylase SIRT3. TCA, tricarboxylic acid cycle. (From Rey and Reddy. 2013. Science. 342:570-571. Reprinted with permission from AAAS.) Circadian regulation of mitochondrial oxidative metabolism, and what happens when you eliminate the mitochondrial calcium uniporter