Abstract
Therapeutic activation of mitochondrial function has been suggested as an effective strategy to combat aging. Hydralazine is an FDA-approved drug used in the treatment of hypertension, heart failure and cancer. Hydralazine has been recently shown to promote lifespan in C. elegans, rotifer and yeast through a mechanism which has remained elusive. Here we report cAMP-dependent protein kinase (PKA) as the direct target of hydralazine. Using in vitro and in vivo models, we demonstrate a mechanism in which binding and stabilization of a catalytic subunit of PKA by hydralazine lead to improved mitochondrial function and metabolic homeostasis via the SIRT1/SIRT5 axis, which underlies hydralazine’s prolongevity and stress resistance benefits. Hydralazine also protects mitochondrial metabolism and function resulting in restoration of health and lifespan in C. elegans under high glucose and other stress conditions. Our data also provide new insights into the mechanism(s) that explain various other known beneficial effects of hydralazine.
Highlights
Therapeutic activation of mitochondrial function has been suggested as an effective strategy to combat aging
Quantitative PCR measurement of NADH dehydrogenase subunit 5 (MT-ND5) and mitochondrial encoded ribosomal RNAs (MT-RNR) in DNA extracted from hydralazine-treated cells (5 μM for 72 h) showed an increase in the mtDNA/nDNA ratio (Fig. 1b)
We showed that hydralazine-mediated life and healthspan extension and protection against rotenone toxicity in
Summary
Therapeutic activation of mitochondrial function has been suggested as an effective strategy to combat aging. Using in vitro and in vivo models, we demonstrate a mechanism in which binding and stabilization of a catalytic subunit of PKA by hydralazine lead to improved mitochondrial function and metabolic homeostasis via the SIRT1/SIRT5 axis, which underlies hydralazine’s prolongevity and stress resistance benefits. Hydralazine protects mitochondrial metabolism and function resulting in restoration of health and lifespan in C. elegans under high glucose and other stress conditions. The mammalian sirtuin family of proteins (SIRT1-SIRT7) has been the focus of many studies for their perceived regulatory role in a wide variety of cellular processes, including cellular metabolism and aging[6]. SIRT1 and mitochondrial sirtuins (SIRT3-SIRT5) appear to play pivotal roles in maintaining mitochondrial function, and their age-related decline correlates with the pathophysiology of aging[10]. Cyclic AMP (cAMP), one of the most versatile second messenger molecules, plays critical roles in many biological processes
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