Complex I assembly into supercomplexes determines differential mitochondrial ROS production in neurons and astrocytes

Author:

Lopez-Fabuel IreneORCID,Le Douce Juliette,Logan Angela,James Andrew M.,Bonvento Gilles,Murphy Michael P.,Almeida AngelesORCID,Bolaños Juan P.

Abstract

Neurons depend on oxidative phosphorylation for energy generation, whereas astrocytes do not, a distinctive feature that is essential for neurotransmission and neuronal survival. However, any link between these metabolic differences and the structural organization of the mitochondrial respiratory chain is unknown. Here, we investigated this issue and found that, in neurons, mitochondrial complex I is predominantly assembled into supercomplexes, whereas in astrocytes the abundance of free complex I is higher. The presence of free complex I in astrocytes correlates with the severalfold higher reactive oxygen species (ROS) production by astrocytes compared with neurons. Using a complexomics approach, we found that the complex I subunit NDUFS1 was more abundant in neurons than in astrocytes. Interestingly, NDUFS1 knockdown in neurons decreased the association of complex I into supercomplexes, leading to impaired oxygen consumption and increased mitochondrial ROS. Conversely, overexpression of NDUFS1 in astrocytes promoted complex I incorporation into supercomplexes, decreasing ROS. Thus, complex I assembly into supercomplexes regulates ROS production and may contribute to the bioenergetic differences between neurons and astrocytes.

Funder

Ministerio de Economía y Competitividad

Ministry of Economy and Competitiveness | Instituto de Salud Carlos III

Seventh Framework Programme

European Commission

HHS | NIH | National Institute on Drug Abuse

Publisher

Proceedings of the National Academy of Sciences

Subject

Multidisciplinary

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