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 Ca 2+ uptake plays an essential role in the control of aerobic metabolism. Mitochondrial Ca 2+ accumulation stimulates aerobic metabolism by inducing the activity of three TCA cycle dehydrogenases. In detail, matrix Ca 2+ 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 Ca 2+ 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 Ca 2+ uptake in the heart, a high-energy consuming organ whose function strictly depends on appropriate Ca 2+ signaling.

Mitochondria at Work: New Insights into Regulation and Dysregulation of Cellular Energy Supply and Metabolism

“…This allows fine-tuning of aerobic metabolism. Mitochondrial Ca 2+ accumulation stimulates aerobic metabolism by inducing the activity of three TCA cycle dehydrogenases: pyruvate dehydrogenases, isocitrate dehydrogenase, and α-ketoglutarate dehydrogenase [ 28 ]. The endoplasmic reticulum chaperon calnexin was reported to control the cellular energy balance between OXPHOS and glycolysis.…”

Inflammation-Induced Protein Unfolding in Airway Smooth Muscle Triggers a Homeostatic Response in Mitochondria

“…In ASM, the TNFα-induced increase in force and ATP consumption stimulates F1Fo-ATPase/ATP synthase (complex V) activity and increases O 2 consumption and ATP production in mitochondria. Based on biochemical studies, it is well known that mitochondrial production of ATP (oxidative phosphorylation) also depends on dehydrogenase enzyme activities of the TCA cycle, particularly pyruvate dehydrogenase (PDH), NAD-isocitrate dehydrogenase (ICDH), and oxoglutarate dehydrogenase (OGDH), which are Ca 2+ dependent [ 54 , 55 , 56 , 57 , 58 ]. Additionally, an increase in [Ca 2+ ] cyt increases NADH levels in the mitochondria by stimulating mitochondrial shuttle systems such as the glycerol phosphate shuttle and the aspartate/glutamate transporters [ 59 , 60 , 61 ].…”

Organization of the Respiratory Supercomplexes in Cells with Defective Complex III: Structural Features and Metabolic Consequences

“…However, several other important pathways are associated with mitochondria, such as the citric acid cycle [1,2], the fatty acids oxidation [3] and lipid droplets formation [4], the iron-sulfur (Fe-S) protein biogenesis [5] and amino acids catabolism [6]. Furthermore, mitochondria are implicated in the buffering of cytosolic calcium concentration [7], in generation of reactive oxygen species (ROS) [8], and in regulation and execution of different types of cell death [9]. They are also involved in an array of adaptive responses triggered by perturbations of intracellular homeostasis [10], orchestrating anabolic and catabolic reactions, which are finely adjusted according to different cytosolic conditions.…”