Metabolite regulation of the mitochondrial calcium uniporter channel

Abstract

Calcium (Ca²⁺) is known to stimulate mitochondrial bioenergetics through the modulation of TCA cycle dehydrogenases and electron transport chain (ETC) complexes. This is hypothesized to be an essential pathway of energetic control to meet cellular ATP demand. While regulatory mechanisms of mitochondrial calcium uptake have been reported, it remains unknown if metabolite flux itself feedsback to regulate mitochondrial calcium (_mCa²⁺) uptake. This hypothesis was recently tested by Nemani et al. (Sci. Signal. 2020) where the authors report that TCA cycle substrate flux regulates the mitochondrial calcium uniporter channel gatekeeper, mitochondrial calcium uptake 1 (MICU1), gene transcription in an early growth response protein 1 (EGR1) dependent fashion. They posit this is a regulatory feedback mechanism to control ionic homeostasis and mitochondrial bioenergetics with changing fuel availability. Here, we provide a historical overview of mitochondrial calcium exchange and comprehensive appraisal of these results in the context of recent literature and discuss possible regulatory pathways of _mCa²⁺ uptake and mitochondrial bioenergetics.

Keywords: Calcium; Energetics; MCU; MICU1; MPC; Mitochondria; OXPHOS; TCA cycle; TCA substrates.

Fig. 1.. Diagram of a proposed regulatory feedback mechanism to regulate mitochondrial energetics in the face of changing fuel supply.

Mitochondrial metabolites signal transcriptional machinery through an unknown mechanism to regulate MICU1 expression. MICU1 activity may also be modulated by protein quality control, or post-translational modifications (PTMs). MICU1 gene expression leads to a change in mtCU gating, which subsequently modulates uptake and matrix _mCa²⁺ levels. _mCa²⁺ directly regulates the activity of TCA dehydrogenases (PDH, ICDH, and KDH), perhaps the ETC and autophagy to modulate ATP production. The proposed feedback regulation is a mechanism to match mitochondrial energetic output with fuel supply. TCA, tricarboxylic acid cycle; PTMs, post-translational modifications; MICU1, mitochondrial calcium uptake 1; mtCU, mitochondrial calcium uniporter complex; _mCa²⁺, mitochondrial calcium; ETC, electron transport chain; ATP, adenosine triphosphate.

Fig. 2.. Schematic of the various molecular events proposed to comprise a feedback regulatory loop between TCA substrates and _mCa²⁺ exchange and ATP production.

(1) TCA substrates are transported by specific metabolite carrier/exchanger systems present at the IMM. (2) TCA metabolite levels in the mitochondrial matrix influence overall TCA cycle flux and reducing equivalents supplied to the ETC. (3) Changes in substrate availability or fuel utilization (stress) signal via an unknown mechanism (?) to induce transcription or protein quality control systems to modulate MICU1 protein levels. (4) An unknown molecular sensor signals EGR1 to upregulate MICU1 transcription. (5) Increased MICU1 augments mtCU gating and _mCa²⁺ uptake, which subsequently modulates matrix Ca²⁺ levels. (6) _mCa²⁺ directly regulates the TCA cycle dehydrogenases (PDH, IDH, and aKDH) to modulate activity and reducing equivalent supply to the ETC to modify mitochondrial energy output in terms of ATP production. CPT1, carnitine palmitoyltransferase 1; CPT2, carnitine palmitoyltransferase 2; MPC, mitochondrial pyruvate carrier; MCU, mitochondrial calcium uniporter; MICU1, mitochondrial calcium uptake 1; EGR1, early growth response 1; OMM, outer mitochondrial membrane; IMS, intermembrane space; IMM, inner mitochondrial membrane (IMM).