Partially Inhibiting Mitochondrial Complex I as an Approach to Therapy

Manipulation of cellular biochemistry in order to provoke beneficial stress responses, in a similar way to the outcome of calorie restriction, heat and cold stress, oxidative stress, and so forth, is a popular area of development in aging research. It dovetails well with the established infrastructure for discovering and vetting small molecule drugs, and there are many potential points of intervention in signaling pathways in a cell. Unfortunately the effect sizes leave something to be desired; few pharmacological approaches to stress response upregulation come with evidence to suggest that they are an improvement over exercise or the practice of calorie restriction.

One of the better explored approaches to inducing a stress response in cells is the selective inhibition of mitochondrial function. Mitochondria are the power plants of the cell. Given that mitochondrial function is of great importance to health, and declines with age, mitochondrial inhibition is a counterintuitive path to therapy, but it works. Some forms of partial impairment of the operation of the electron transport chain in mitochondria, a collection of protein complexes responsible for producing chemical energy store molecules to power cellular processes, lead to a stress response that produces a net benefit in older individuals. In particular mitochondrial function can be diminished in aging by a faltering of the quality control mechanism of mitophagy, responsible for removing worn and damaged mitochondria. If partial inhibition then provokes more effective mitophagy, the result is a net gain.

Mitochondrial complex I as a therapeutic target for Alzheimer's disease

Partial inhibition of complex I with small molecules emerged as a promising strategy to induce beneficial mitochondrial induced stress response. Complex I inhibitors are in clinical trials for various human conditions, including type 2 diabetes, cancers, metabolic disorder, obesity, inflammatory and infectious diseases. Only metformin, resveratrol, berberine, and epigallocatechin-3-gallate were trialed in a limited number of studies for neurodegenerative diseases, including Alzheimer's disease (AD). Metformin improved cognitive function in patients with amnestic MCI, while resveratrol, berberine and epigallocatechin-3-gallate did not show statistically significant improvements in cognitive performance in patients with AD, Huntington's disease, or MCI. While all four complex I inhibitors penetrate the blood-brain barrier (BBB), the therapeutic effect of resveratrol, berberine and epigallocatechin-3-gallate was limited, probably due to a poor stability, short half-life, and a very low bioavailability in contrast to metformin. Therefore, modifications of current complex I inhibitors or the development of new small molecules with improved drug-like properties and bioavailability are needed to increase therapeutic efficacy for neurodegenerative diseases.

We recently identified a small molecule tricyclic pyrone compound (CP2) that penetrates the BBB and accumulates in mitochondria where it mildly inhibits the activity of complex I. CP2 is bioavailable, has low toxicity in vitro and in vivo, and has good drug-like properties and safety profile. CP2 increased mitochondrial respiratory control ratio and reduced proton leak, suggesting better coupling efficiency of the neuronal electron transport chain (ETC), greater bioenergetic reserve, and enhanced ability to withstand stress. In vivo efficacy of chronic CP2 administration was examined in independent cohorts of male and female mouse models of AD. In all studies, chronic CP2 treatment did not induce toxicity or affect development. Remarkably, in all treatment groups, CP2 improved energy homeostasis in the brain and periphery (glucose uptake and utilization, glucose tolerance, and insulin resistance), synaptic activity, long-term potentiation, dendritic spine maturation, cognitive function and proteostasis (reduced amyloid-β and phosphorylated Tau levels), and reduced oxidative stress and inflammation in the brain and periphery, ultimately blocking the ongoing neurodegeneration.

In conclusion, we summarized here evidence for a novel therapeutic approach to exploit the incredible ability of mitochondria to engage multifaceted neuroprotective stress response triggered by partial complex I inhibition. This approach promises relief for multiple human conditions, and to promote healthy aging to delay the onset of neurogenerative diseases, AD in particular, where age is the greatest risk factor. There is a mounting body of evidence generated in model organisms and humans in support of the safety of chronic application of complex I inhibitors. However, a better understanding of the molecular mechanisms is required to establish safety in translation to humans, including the development of biomarkers that inform on mitochondrial function and the capacity to induce the beneficial stress response. Further therapeutic developments should produce selective and specific complex I inhibitors capable of penetrating the BBB with excellent safety profile.

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