Most mitochondrial dGTP is tightly bound to respiratory complex I through the NDUFA10 subunit
Molina-Granada, David (Vall d'Hebron Institut de Recerca (VHIR))
González-Vioque, Emiliano (Vall d'Hebron Institut de Recerca (VHIR))
Dibley, Marris G. (Monash University. Department of Biochemistry and Molecular Biology)
Cabrera-Pérez, Raquel (Vall d'Hebron Institut de Recerca (VHIR))
Vallbona-Garcia, Antoni (Vall d'Hebron Institut de Recerca (VHIR))
Torres-Torronteras, Javier (Centro de Investigación Biomédica en Red de Enfermedades Raras)
Sazanov, Leonid A. (Institute of Science and Technology Austria)
Ryan, Michael T. (Monash University. Department of Biochemistry and Molecular Biology)
Cámara, Yolanda (Vall d'Hebron Institut de Recerca (VHIR))
Martí, Ramon A. (Vall d'Hebron Institut de Recerca (VHIR))
Universitat Autònoma de Barcelona

Data:	2022
Resum:	Imbalanced mitochondrial dNTP pools are known players in the pathogenesis of multiple human diseases. Here we show that, even under physiological conditions, dGTP is largely overrepresented among other dNTPs in mitochondria of mouse tissues and human cultured cells. In addition, a vast majority of mitochondrial dGTP is tightly bound to NDUFA10, an accessory subunit of complex I of the mitochondrial respiratory chain. NDUFA10 shares a deoxyribonucleoside kinase (dNK) domain with deoxyribonucleoside kinases in the nucleotide salvage pathway, though no specific function beyond stabilizing the complex I holoenzyme has been described for this subunit. We mutated the dNK domain of NDUFA10 in human HEK-293T cells while preserving complex I assembly and activity. The NDUFA10 E160A/R161A shows reduced dGTP binding capacity in vitro and leads to a 50% reduction in mitochondrial dGTP content, proving that most dGTP is directly bound to the dNK domain of NDUFA10. This interaction may represent a hitherto unknown mechanism regulating mitochondrial dNTP availability and linking oxidative metabolism to DNA maintenance. Mitochondrial dGTP is mostly bound to an accessory subunit of complex I of the mitochondrial respiratory chain, which may reveal a mechanism linking mitochondrial dNTP availability and oxidative metabolism.
Ajuts:	Ministerio de Economía y Competitividad BFU2014-52618-R Agencia Estatal de Investigación SAF2017-87506 Agencia Estatal de Investigación PID2020-112929RB-I00
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	Biochemistry ; Molecular medicine
Publicat a:	Communications Biology, Vol. 5 (june 2022) , ISSN 2399-3642

DOI: 10.1038/s42003-022-03568-6
PMID: 35739187

16 p, 2.2 MB

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