The Mitochondrial Ca2+ Uptake and the Fine-Tuning of Aerobic Metabolism

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.

Keywords: aerobic metabolism; mitochondria; mitochondrial calcium uniporter (MCU); mitochondrial calcium uptake; systemic metabolism.