Reverse electron transfer is activated during aging and contributes to aging and age‐related disease. (16th February 2023)

• Record Type: Journal Article
• Authors: Rimal, Suman; Tantray, Ishaq; Li, Yu; Pal Khaket, Tejinder; Li, Yanping; Bhurtel, Sunil; Li, Wen; Zeng, Cici; Lu, Bingwei
• Is Part Of: EMBO reports. Volume 24:Number 4(2023)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2023-02-16
• Subjects: Alzheimer's disease -- lifespan -- mitochondrial complex I -- NAD+/NADH ratio -- reverse electron transport; Molecular biology -- Periodicals; Molecular Biology -- Periodicals; Molecular biology; Periodicals; 572.8
• DOI: 10.15252/embr.202255548
• Languages: English
• ISSNs: 1469-221X

Abstract

Abstract: Mechanisms underlying the depletion of NAD + and accumulation of reactive oxygen species (ROS) in aging and age‐related disorders remain poorly defined. We show that reverse electron transfer (RET) at mitochondrial complex I, which causes increased ROS production and NAD + to NADH conversion and thus lowered NAD + /NADH ratio, is active during aging. Genetic or pharmacological inhibition of RET decreases ROS production and increases NAD + /NADH ratio, extending the lifespan of normal flies. The lifespan‐extending effect of RET inhibition is dependent on NAD + ‐dependent Sirtuin, highlighting the importance of NAD + /NADH rebalance, and on longevity‐associated Foxo and autophagy pathways. RET and RET‐induced ROS and NAD + /NADH ratio changes are prominent in human induced pluripotent stem cell (iPSC) model and fly models of Alzheimer's disease (AD). Genetic or pharmacological inhibition of RET prevents the accumulation of faulty translation products resulting from inadequate ribosome‐mediated quality control, rescues relevant disease phenotypes, and extends the lifespan of Drosophila and mouse AD models. Deregulated RET is therefore a conserved feature of aging, and inhibition of RET may open new therapeutic opportunities in the context of aging and age‐related diseases including AD. Synopsis: Reverse electron transport (RET) at mitochondrial complex I generates reactive oxygen species (ROS) and reduces NAD + /NADH ratio. Inhibition of RET genetically or pharmacologically extends animal lifespan and ameliorates Alzheimer's disease‐related phenotypes. RET is activated in aged Drosophila and Drosophila models of Alzheimer's disease (AD) Inhibition of RET using a small molecule drug CPT or by knocking down its target mitochondrial complex I subunit NDUFS3 extends lifespan in Drosophila and mice. Inhibition of RET rescues AD‐related disease phenotypes in Drosophila and mouse models RET is also active in human iPSC models of AD. Abstract : Reverse electron transport (RET) at mitochondrial complex I generates reactive oxygen species (ROS) and reduces NAD + /NADH ratio. Inhibition of RET genetically or pharmacologically extends animal lifespan and ameliorates Alzheimer's disease‐related phenotypes.