MCU genetically altered mice suggest how mitochondrial Ca2+ regulates metabolism

Abstract

Skeletal muscle has a major impact on total body metabolism and obesity, and is characterized by dynamic regulation of substrate utilization. While it is accepted that acute increases in mitochondrial matrix Ca²⁺ increase carbohydrate usage to augment ATP production, recent studies in mice with deleted genes for components of the mitochondrial Ca²⁺ uniporter (MCU) complex have suggested a more complicated regulatory scenario. Indeed, mice with a deleted Mcu gene in muscle, which lack acute mitochondrial Ca²⁺ uptake, have greater fatty acid oxidation (FAO) and less adiposity. By contrast, mice deleted for the inhibitory Mcub gene in skeletal muscle, which have greater acute mitochondrial Ca²⁺ uptake, antithetically display reduced FAO and progressive obesity. In this review we discuss the emerging concept that dynamic fluxing of mitochondrial matrix Ca²⁺ regulates metabolism.

Keywords: Ca(2+) signaling; metabolism; mitochondria; obesity; skeletal muscle.

Figure 1.. Striated muscle Ca²⁺ cycling and excitation-contraction coupling.

In skeletal muscle the action potential from the plasma membrane propagates along the transverse tubule (T-tubule) and directly activates L-type Ca²⁺ channels by mechanical coupling with the ryanodine receptor (RyR) in the sarcoplasmic reticulum (SR) membrane, while in heart there is chemical coupling by Ca²⁺ influx through L-type Ca²⁺ channels that stimulates Ca²⁺ release form over-riding RyR channels, which dumps copious amounts of Ca²⁺ into the cytosol. Elevated cytosolic Ca²⁺ levels trigger muscle contraction by facilitating the binding of Ca²⁺ to the myofilament protein troponin C, and ATP produced by mitochondria enables the power-stroke whereby the myosin heads mechanically pull actin thin filaments. Resting cytosolic Ca²⁺ levels are restored by reuptake into the SR via sarcoplasmic reticulum Ca²⁺-ATPase (SERCA) pump, and a minor role for export of Ca²⁺ out of the cell through the Na⁺/Ca²⁺ exchanger (NCX). Mitochondrial Ca²⁺ influx occurs through the MCU complex and efflux is thought to occur through Na⁺/Ca²⁺/Li⁺ exchanger (NCLX). Acute elevation in mitochondrial matrix Ca²⁺ levels during contraction can enhance the activity of pyruvate dehydrogenase (PDH), malate dehydrogenase (MDH), 2-oxoglutarate dehydrogenase (OGDH), and NADP⁺-dependent isocitrate dehydrogenase (ICDH) complexes, as well as augment the activity of the electron transport chain components. Mitochondria located adjacent to the SR (tethering proteins) experience a much larger effective concentration of Ca²⁺ that can effect MCU influx. Adapted from “Cardiomyocyte Energetics”, by BioRender.com (2024). Retrieved from https://app.biorender.com/biorender-templates.

Figure 2. Key Figure.. Acute vs long-term Ca²⁺ regulation on substrate use through MCU.

(Left panel), MCU acutely promotes increased mitochondrial matrix Ca²⁺ influx, enhancing PDH activity while decreasing PDK4 levels, and eventually leading to increased glycolysis and glucose oxidation. (Right panel), inhibiting MCU reduces acute mitochondrial Ca²⁺ influx, impairing acute PDH activity while increasing PDK4 levels, leading to impaired glycolysis. However, this reduced mitochondrial Ca²⁺ flux rewires substrate use towards greater fatty acid oxidation (FAO) by reducing malonyl CoA level and relieving inhibition of the carnitine palmitoyltransferase-I (CPT-I) enzyme to allow greater FA influx. This figure was created using BioRender (https://biorender.com/).