Inhibiting cytosolic translation and autophagy improves health in mitochondrial disease

Abstract

Mitochondrial respiratory chain (RC) disease therapies directed at intra-mitochondrial pathology are largely ineffective. Recognizing that RC dysfunction invokes pronounced extra-mitochondrial transcriptional adaptations, particularly involving dysregulated translation, we hypothesized that translational dysregulation is itself contributing to the pathophysiology of RC disease. Here, we investigated the activities, and effects from direct inhibition, of a central translational regulator (mTORC1) and its downstream biological processes in diverse genetic and pharmacological models of RC disease. Our data identify novel mechanisms underlying the cellular pathogenesis of RC dysfunction, including the combined induction of proteotoxic stress, the ER stress response and autophagy. mTORC1 inhibition with rapamycin partially ameliorated renal disease in B6.Pdss2(kd/kd) mice with complexes I-III/II-III deficiencies, improved viability and mitochondrial physiology in gas-1(fc21) nematodes with complex I deficiency, and rescued viability across a variety of RC-inhibited human cells. Even more effective was probucol, a PPAR-activating anti-lipid drug that we show also inhibits mTORC1. However, directly inhibiting mTORC1-regulated downstream activities yielded the most pronounced and sustained benefit. Partial inhibition of translation by cycloheximide, or of autophagy by lithium chloride, rescued viability, preserved cellular respiratory capacity and induced mitochondrial translation and biogenesis. Cycloheximide also ameliorated proteotoxic stress via a uniquely selective reduction of cytosolic protein translation. RNAseq-based transcriptome profiling of treatment effects in gas-1(fc21) mutants provide further evidence that these therapies effectively restored altered translation and autophagy pathways toward that of wild-type animals. Overall, partially inhibiting cytosolic translation and autophagy offer novel treatment strategies to improve health across the diverse array of human diseases whose pathogenesis involves RC dysfunction.

Modulating Mitophagy in Mitochondrial Disease

“…Of these lithium is known to be an inhibitor of mitophagy [64]. Lysosomal inhibitors also slow autophagy and mitophagy, the antimalarial drug, chloroquine, being a well-known example that prevents lysosomal acidification and proteolysis [65].…”

Nutritional interventions in primary mitochondrial disorders: Developing an evidence base

“…However, RC disease also results in deficiencies of NAD + and uridine, as well as excessive free radical production. In particular, a relative increase in the ratio of reduced NAD + (NADH) to NAD + [103], as well as absolute deficiencies of both of these essential redox metabolites [104], alters flux through hundreds of downstream metabolic pathways, including amino acid metabolism [97]. Targeted blood metabolite analyses in 19 patients with RC disease identified that they have an almost two-fold increase in the ratio of several amino acids when normalized to glutamate as compared to healthy individuals [105].…”

“…This highly conserved signaling network functions to collectively sense the cellular nutrient and health status to enable cells to make the ultimate decision to either grow or die, where these essential activities are coordinated by the signaling network to mediate the specific response of hundreds of downstream biological processes and biochemical pathways [99]. For example, RC inhibition alters the expression and ability of glucose to inhibit FOX01 [100], activates AMPK and mTORC1 [104] and inhibits PPAR family gene activity in different tissues, key signaling and regulatory pathways for cellular function [100]. Many of these signaling changes can be reversed by treating cells with glucose [104] as well as by a range of drugs that target their specific activities [104, 106].…”

“…For example, RC inhibition alters the expression and ability of glucose to inhibit FOX01 [100], activates AMPK and mTORC1 [104] and inhibits PPAR family gene activity in different tissues, key signaling and regulatory pathways for cellular function [100]. Many of these signaling changes can be reversed by treating cells with glucose [104] as well as by a range of drugs that target their specific activities [104, 106]. With these insights, providing proper cellular nutrition, such as glucose itself, can be viewed as a potential therapy to normalize cell signaling responses and thereby improve the cellular capacity to survive and function in RC disease [104].…”

“…Many of these signaling changes can be reversed by treating cells with glucose [104] as well as by a range of drugs that target their specific activities [104, 106]. With these insights, providing proper cellular nutrition, such as glucose itself, can be viewed as a potential therapy to normalize cell signaling responses and thereby improve the cellular capacity to survive and function in RC disease [104]. Systematically characterizing and therapeutically targeting central alterations in the nutrient-sensing signaling network may offer a personalized means to reverse the global sequelae caused by RC dysfunction to improve patient health outcomes.…”