Reverse electron transfer is activated during aging and contributes to aging and age‐related disease

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.

Reverse Electron Transport at Mitochondrial Complex I in Ischemic Stroke, Aging, and Age-Related Diseases

“…These data suggest that mitochondrial complex I involved in RET may adopt a different conformation than the complex I involved in FET. Similar protein-protein interaction changes were observed during normal Drosophila aging [47], suggesting a general mechanism of RET deregulation. Notch, therefore, becomes the first protein not belonging to the ETC to be recruited to complex I and directly participate in RET.…”

“…RET inhibition by CPT treatment extended the lifespan and rescued the brain tumor and AD phenotypes in these settings. Moreover, the partial knockdown of NDUFS3 has similar protective effects as CPT in the contexts of aging, brain tumor, and AD, and CPT treatment in the NDUFS3 knockdown condition did not offer additional benefits [ 47 , 89 ], supporting the assertion thatCPT specifically engages with RET through NDUFS3 in vivo to offer its biological benefits. Importantly, the effect of CPT in aging, age-related AD pathogenesis, and brain tumor settings can be faithfully recapitulated by the supplementation of the NAD + precursors of nicotinamide mononucleotide (NMN) and nicotinamide riboside (NR), supporting the notion that the NAD + /NADH ratio is a key mediator of the biological effects of RET inhibition by CPT.…”

“…Given that increased ROS and decreased NAD + levels and, thus, a lowered NAD + /NADH ratio, the key outcomes of RET, are hallmarks of aging, it is possible that RET is activated during normal aging. Indeed, this was found to be the case in Drosophila [47]. Moreover, in a Drosophila model of a Notch-induced brain tumor [87,88], RET was also found to be elevated.…”

“…Mitochondrial dysfunction during stroke is also associated with multiple proteomic changes present in complex I proteins (e.g., NDUFS3, V1, V2, S1, S2). Such changes also occur during aging and age-related neurodegeneration [ 47 ], and may be responsible for RET and RET-ROS production during ischemic reperfusion (see later). Mitochondrial complex I, the first protein complex of the mitochondrial respiratory chain (MRC) that is also known as NADH dehydrogenase, is potentially involved in various neurodegenerative disorders through excessive ROS generation and modulating membrane polarization [ 48 , 49 ].…”

“…Compromised complexIII and IV functions could lead to increased RET and contribute to AD pathology, although this remains to be directly demonstrated using clinical samples. However, recent studies in Drosophila models of AD expressing full-length amyloid precursor proteins (APPs) or the C-terminal fragment of APP (APP.C99), or in human induced pluripotent stem cell (iPSC)-derived neuronal models of AD, showed that RET was activated, as demonstrated by the increased production of RET-ROS and decreased NAD + /NADH ratio [ 47 ].…”