Abstract
Recently, the role of mitochondrial activity in high-energy demand organs and in the orchestration of whole-body metabolism has received renewed attention. In mitochondria, pyruvate oxidation, ensured by efficient mitochondrial pyruvate entry and matrix dehydrogenases activity, generates acetyl CoA that enters the TCA cycle. TCA cycle activity, in turn, provides reducing equivalents and electrons that feed the electron transport chain eventually producing ATP. Mitochondrial Ca2+ uptake plays an essential role in the control of aerobic metabolism. Mitochondrial Ca2+ accumulation stimulates aerobic metabolism by inducing the activity of three TCA cycle dehydrogenases. In detail, matrix Ca2+ indirectly modulates pyruvate dehydrogenase via pyruvate dehydrogenase phosphatase 1, and directly activates isocitrate and α-ketoglutarate dehydrogenases. Here, we will discuss the contribution of mitochondrial Ca2+ uptake to the metabolic homeostasis of organs involved in systemic metabolism, including liver, skeletal muscle, and adipose tissue. We will also tackle the role of mitochondrial Ca2+ uptake in the heart, a high-energy consuming organ whose function strictly depends on appropriate Ca2+ signaling.
Highlights
Intracellular Ca2+ plays a significant role as a second messenger controlling both ubiquitous and tissue-specific processes
Ca2+ influx into energized mitochondria depends on the electrochemical gradient (Deluca and Engstrom, 1961; Vasington and Murphy, 1962) and it is ensured by the activity of the Mitochondrial Calcium Uniporter (MCU), a highly selective channel of the inner mitochondrial membrane (IMM) (Kirichok et al, 2004; Baughman et al, 2011; De Stefani et al, 2011)
These regulators belong to the MICU family that comprises MICU1, MICU2 and MICU3, each of them characterized by different expression patterns and specific functions
Summary
Intracellular Ca2+ plays a significant role as a second messenger controlling both ubiquitous and tissue-specific processes. Ca2+ influx into energized mitochondria depends on the electrochemical gradient (Deluca and Engstrom, 1961; Vasington and Murphy, 1962) and it is ensured by the activity of the Mitochondrial Calcium Uniporter (MCU), a highly selective channel of the IMM (Kirichok et al, 2004; Baughman et al, 2011; De Stefani et al, 2011). Microdomains of high Ca2+ concentration in sites of close proximity between the ER/SR and the mitochondria, the so-called mitochondrial-associated membranes (MAMs), are generated upon Ca2+ release from the ER/SR (endoplasmic/sarcoplasmic reticulum) stores, ensuring rapid mitochondrial Ca2+ entry (Rizzuto et al, 1993, 1998). We will discuss the role of mitochondrial Ca2+ signaling in the control of cell metabolism, with particular emphasis on those organs involved in the regulation of systemic metabolism, including liver, skeletal muscle, and adipose tissue. We will discuss studies based on the genetic modulation of MCU activity, both in cell lines and in animal models
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