Pro-Longevity Kynurenine Pathway Interventions Modulate Mitochondrial Dynamics in C. elegans

Abstract

Aging is a conserved phenomenon that affects many eukaryotic systems. Aging can be defined as the gradual, chronic loss of function in many biological processes that ultimately lead to the death of an organism. Mitochondria are entangled in the aging paradigm in eukaryotic systems. In healthy organisms, mitochondria are a dynamic network of membrane bound organelles that generate the cell’s preferred potential energy source, ATP. Mitochondrial dysfunction is one of the nine hallmarks of aging (1). Mitochondrial dysfunction impacts the other eight hallmarks of aging either directly or indirectly (2). The dynamic structure of mitochondria, i.e., the degree of interconnectedness or fragmentation of the mitochondrial network, is regulated by the two opposing processes of mitochondrial fission and fusion. Mitochondrial fission occurs when there is an excess of nutrients or oxidative stress and results in spherical, fragmented mitochondrial networks. Fusion occurs under caloric restriction, a known pro-longevity intervention, and results in elongated, tubular mitochondrial networks. The kynurenine pathway is the de novo synthesis pathway of nicotinamide adenine dinucleotide (NAD+) from exogenous tryptophan. Impairing the activity of the kynurenine pathway enzymes 3-hydroxyanthranilic acid (HAAO) and kynureninase (KYNU) increases lifespan in Caenorhabditis elegans by 20-30%. Adding exogenous 3-hydroxyanthranilic acid (3HAA), the metabolite generated by KYNU and degraded by HAAO, increases lifespan to a similar degree to knocking out HAAO inhibition. Mitochondrial function and the kynurenine pathway are connected by NAD+ as it is a product of the kynurenine pathway and used as an electron carrier for the electron transport chain in the mitochondria. Mitochondrial function and structure have not previously been characterized in the context of pro-longevity kynurenine pathway interventions. In this work I examine mitochondrial function and structure when subjected to kynurenine pathway inhibition. Kynurenine pathway modulation results in slight mitochondrial dysfunction middle in life as measured by O2 consumption assays. Mitochondrial fragmentation is observed when C. elegans are treated with kynurenine pathway modulation. This work should establish a link between kynurenine pathway inhibition and mitochondrial function in the context of aging.