Mitochondrial aconitase controls adipogenesis through mediation of cellular ATP production

Abstract

Mitochondrial aconitase (Aco2) catalyzes the conversion of citrate to isocitrate in the TCA cycle, which produces NADH and FADH2, driving synthesis of ATP through OXPHOS. In this study, to explore the relationship between adipogenesis and mitochondrial energy metabolism, we hypothesize that Aco2 may play a key role in the lipid synthesis. Here, we show that overexpression of Aco2 in 3T3-L1 cells significantly increased lipogenesis and adipogenesis, accompanied by elevated mitochondrial biogenesis and ATP production. However, when ATP is depleted by rotenone, an inhibitor of the respiratory chain, the promotive role of Aco2 in adipogenesis is abolished. In contrast to Aco2 overexpression, deficiency of Aco2 markedly reduced lipogenesis and adipogenesis, along with the decreased mitochondrial biogenesis and ATP production. Supplementation of isocitrate efficiently rescued the inhibitory effect of Aco2 deficiency. Similarly, the restorative effect of isocitrate was abolished in the presence of rotenone. Together, these results show that Aco2 sustains normal adipogenesis through mediating ATP production, revealing a potential mechanistic link between TCA cycle enzyme and lipid synthesis. Our work suggest that regulation of adipose tissue mitochondria function may be a potential way for combating abnormal adipogenesis related diseases such as obesity and lipodystrophy. K E Y W O R D S cell differentiation, mitochondrial metabolism, TCA cycle | 6689 CHEN Et al.

Emerging Role of TCA Cycle-Related Enzymes in Human Diseases

“…Aconitase 1 (Aco1) and aconitase 2 (Aco2), two aconitase isoforms, present in the cytoplasm and mitochondria, respectively [ 18 ]. Deficiency of Aco1 and Aco2 are associated with increased risk of optic atrophy and encephalopathy, respectively [ 21 , 22 ]. These diseases are caused by autosomal recessive mutations in Aco 1 and 2.…”

Comparison of urine proteome between obese people and normal weight people

“…In addition, other differential proteins have been reported to be associated with metabolism or obesity. Aconitate hydratase is involved in tricarboxylic acid cycle and carbohydrate metabolism, catalyzes the isomerization of citrate into isocitrate through cisaconite acid, and can control adipogenesis by mediating the production of cellular ATP [29]. Inhibin and activin can inhibit and activate pituitary secretion of follicle-stimulating hormone, respectively.…”

TRPV4 modulation affects mitochondrial parameters in adipocytes and its inhibition upregulates lipid accumulation

“…Both extra- and intra-cellular ATP levels are shown to modulate adipogenesis [15, 46]. Although mitochondria becomes metabolically active during adipogenesis however a reduction in cellular ATP is reported [47].…”