Metabolic costs and trade-offs of hypermetabolism in human motor neurons with ATP
synthase deficiency
#MMPMID41381852
Torregrosa-Muņumer R
; Turkia J
; Ermi? R
; Kvist J
; Harjuhaahto S
; Pennonen J
; Hietakangas V
; Ylikallio E
; Tyynismaa H
Commun Biol
2025[Dec]; 8
(1
): 1759
PMID41381852
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Hypermetabolism, a futile cycle of energy production and consumption, has been
proposed as an adaptative response to deficiencies in mitochondrial oxidative
phosphorylation. However, the cellular costs of hypermetabolism remain largely
unknown. Here we studied the consequences of hypermetabolism in human motor
neurons harboring a heteroplasmic mutation in MT-ATP6, which impairs ATP synthase
assembly. Respirometry, metabolomics, and proteomics analyses of the motor
neurons showed that elevated ATP production rates were accompanied with increased
demand for acetyl-Coenzyme A (acetyl-CoA) and depleted pantothenate (vitamin B5),
and the proteome was remodeled to support the metabolic adaptation. Mitochondrial
membrane potential and coupling efficiency remained stable, and the therapeutic
agent avanafil did not affect metabolite levels. However, a redistribution of
acetyl-CoA usage resulted in metabolic trade-offs, including reduced histone
acetylation and altered maintenance of the neurotransmitter acetylcholine,
revealing potential vulnerabilities in motor neurons. These findings advance the
understanding of cellular metabolic consequences imposed by hypermetabolic
conditions.
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