Metabolic sensing and control in mitochondria

Abstract

Mitochondria are membrane-enclosed organelles with endosymbiotic origins, harboring independent genomes and a unique biochemical reaction network. To perform their critical functions, mitochondria must maintain a distinct biochemical environment and coordinate with the cytosolic metabolic networks of the host cell. This coordination requires them to sense and control metabolites and respond to metabolic stresses. Indeed, mitochondria adopt feedback or feedforward control strategies to restrain metabolic toxicity, enable metabolic conservation, ensure stable levels of key metabolites, allow metabolic plasticity, and prevent futile cycles. A diverse panel of metabolic sensors mediates these regulatory circuits whose malfunctioning leads to inborn errors of metabolism with mild to severe clinical manifestations. In this review, we discuss the logic and molecular basis of metabolic sensing and control in mitochondria. The past research outlined recurring patterns in mitochondrial metabolic sensing and control and highlighted key knowledge gaps in this organelle that are potentially addressable with emerging technological breakthroughs.

Figure 1.. Mitochondria adopt feedback and feedforward control circuits to achieve metabolic homeostasis or adaptation.

(A) Schematic of a mitochondrial feedback circuit that ensures metabolic conservation by limiting the synthesis of metabolites demanded in mitochondria. PANK2, a mitochondrial enzyme in the Coenzyme A synthesis pathway, is allosterically inhibited by CoA and acetyl-CoA. (B) Schematic of a mitochondrial feedback circuit dedicated to maintaining the mitochondrial levels of a metabolite. Glutathione has been observed to downregulate its mitochondrial importer SLC25A39, functioning in a feedback mechanism likely to achieve homeostatic regulation of mitochondrial glutathione levels. (C) Schematic of a mitochondrial feedback circuit that restrains the production of toxic mitochondrial metabolite. Heme inhibits the import of the rate-limiting enzyme in its de novo synthesis, ALAS1/ALAS2, to avoid the accumulation of toxic porphyrin intermediates. (D) Schematic of a mitochondrial feedforward circuit that enables metabolic plasticity. Urea cycle intermediate arginine stimulates the synthesis of N-acetylglutamate, an allosteric activator of urea cycle enzyme CPS1, allowing robust activation of the urea cycle upon the influx of ammonium nitrogen. (E) Schematic of a mitochondrial feedforward circuit that prevents futile cycles. Fatty acid synthesis substrate malonyl-CoA inhibits the entrance of fatty acid into the reverse reaction, β-oxidation, by allosterically inhibiting CPS1. (F) Schematic of mitochondrial feedforward circuits that trigger adaptive responses to stress. The release of mitochondrial DNA or cytochrome C triggers stress response signaling via the cGAS-STING pathway or the integrated stress response (ISR).

Figure 2.. Molecular basis of metabolite sensing in mitochondria

Schematics for different mechanisms by which metabolites alter the properties of a sensor protein. (A) Metabolites could directly interact with metabolite sensors and modify their behavior through allosteric regulation or post-translational modification. For example, GTP allosterically inhibits glutamate dehydrogenase, which connects the mitochondrial energy state with the replenishment of TCA cycle intermediates. (B) Metabolites could affect enzymatic activity by serving as substrates of protein post-translational modifications. The long-chain acyl-CoA dehydrogenase responds to mitochondrial acetyl-CoA levels via acetylation of residue K42, a reversible modification that reduces its enzymatic activity. (C) Metabolites could modulate the activity of sensor proteins by affecting the incorporation of cofactors and prosthetic groups into apoproteins. Human aminolevulinic acid dehydratase requires an iron-sulfur [4Fe-4S] cluster for its activity, coordinate heme intermediate synthesis with iron availability. (D) The physical properties of mitochondrial membranes are sensitive to their chemical composition, providing a platform for membrane-bound sensor proteins to respond to metabolic stimuli. The cardiolipin-remodeling enzyme Tafazzin preferentially incorporates unsaturated acyl chains into cardiolipin through activation by negative membrane curvature.