Blockade of MCU-Mediated Ca2+ Uptake Perturbs Lipid Metabolism via PP4-Dependent AMPK Dephosphorylation

Abstract

SUMMARY Mitochondrial Ca2+ uniporter (MCU)-mediated Ca2+ uptake promotes the buildup of reducing equivalents that fuel oxidative phosphorylation for cellular metabolism. Although MCU modulates mitochondrial bioenergetics, its function in energy homeostasis in vivo remains elusive. Here we demonstrate that deletion of the Mcu gene in mouse liver (MCUΔhep) and in Danio rerio by CRISPR/Cas9 inhibits mitochondrial Ca2+ (mCa2+) uptake, delays cytosolic Ca2+ (cCa2+) clearance, reduces oxidative phosphorylation, and leads to increased lipid accumulation. Elevated hepatic lipids in MCUΔhep were a direct result of extramitochondrial Ca2+-dependent protein phosphatase-4 (PP4) activity, which dephosphorylates AMPK. Loss of AMPK recapitulates hepatic lipid accumulation without changes in MCU-mediated Ca2+ uptake. Furthermore, reconstitution of active AMPK, or PP4 knockdown, enhances lipid clearance in MCUΔhep hepatocytes. Conversely, gain-of-function MCU promotes rapid mCa2+ uptake, decreases PP4 levels, and reduces hepatic lipid accumulation. Thus, our work uncovers an MCU/PP4/AMPK molecular cascade that links Ca2+ dynamics to hepatic lipid metabolism.

Mitochondrial Calcium Uniporter (MCU) deficiency reveals an alternate path for Ca2+ uptake in photoreceptor mitochondria

“…www.nature.com/scientificreports/ Other candidates for Ca 2+ entry have been described but are not as well-characterized as MCU, as MCU is thought to be primarily responsible for mitochondrial Ca 2+ influx. However, the viability of Mcu -/mice and zebrafish, and the extremely mild consequences of MCU loss in photoreceptors we describe here, suggest that there is an alternative uptake mechanism in at least some cell types 15,47 . Letm1 is a Ca 2+ /H + exchanger on the inner mitochondrial membrane that links Ca 2+ influx and efflux to electron transport chain activity and mitochondrial pH 48 .…”

“…For example, the liver has the important role of synthesizing fatty acids for the body and can also store lipids. In mouse and zebrafish hepatocytes, loss of MCU disrupts lipid metabolism and leads to hepatic lipid accumulation due to delayed cytosolic Ca 2+ clearance and subsequent disrupted AMP-activated protein kinase dephosphorylation 47 . Conversely, in skeletal muscle, loss of MCU causes a metabolic shift towards increased lipid oxidation due to PDH inhibition restricting the availability of pyruvate-derived acetyl-CoA 17,27 .…”

Mitochondrial peptide BRAWNIN is essential for vertebrate respiratory complex III assembly

“…BR levels affect cellular AMPK status. This raises the possibility that BR, through regulation of AMPK activation, might also be involved in regulating intra-hepatic lipid accumulation 40 , a hypothesis that remains to be investigated. Recently, CIII integrity has been implicated in regulatory T cell function and the prevention of autoimmunity 41 , raising the intriguing possibility that BR can also coordinate nutrient availability with immune function.…”

Stem Cells as Drug-like Biologics for Mitochondrial Repair in Stroke

“…Poor metabolism or excess intake of lipids intensifies atherosclerotic plaque buildup and heightens the chance of stroke and ischemic brain injury. The mitochondrial calcium uniporter (MCU) prevents lipid accumulation and maintains appropriate bioenergetics by facilitating oxidative phosphorylation in the mitochondria [68]. However, the loss of MCU activity results in poor oxidative phosphorylation and the accretion of lipids on the arterial wall, thus promoting atherosclerosis and stroke [68].…”

“…The mitochondrial calcium uniporter (MCU) prevents lipid accumulation and maintains appropriate bioenergetics by facilitating oxidative phosphorylation in the mitochondria [68]. However, the loss of MCU activity results in poor oxidative phosphorylation and the accretion of lipids on the arterial wall, thus promoting atherosclerosis and stroke [68]. Therefore, maintaining or enhancing the function of the MCU is another viable mitochondria-based strategy for anti-stroke therapeutics.…”