Abstract
Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS), one of the most common maternally inherited mitochondrial diseases, is caused by mitochondrial DNA mutations that lead to mitochondrial dysfunction. Several treatment options exist, including supplementation with CoQ10, vitamins, and nutrients, but no treatment with proven efficacy is currently available. In this study, we investigated the effects of a novel NAD+ modulator, KL1333, in human fibroblasts derived from a human patient with MELAS. KL1333 is an orally available, small organic molecule that reacts with NAD(P)H:quinone oxidoreductase 1 (NQO1) as a substrate, resulting in increases in intracellular NAD+ levels via NADH oxidation. To elucidate the mechanism of action of KL1333, we used C2C12 myoblasts, L6 myoblasts, and MELAS fibroblasts. Elevated NAD+ levels induced by KL1333 triggered the activation of SIRT1 and AMPK, and subsequently activated PGC-1α in these cells. In MELAS fibroblasts, KL1333 increased ATP levels and decreased lactate and ROS levels, which are often dysregulated in this disease. In addition, mitochondrial functional analyses revealed that KL1333 increased mitochondrial mass, membrane potential, and oxidative capacity. These results indicate that KL1333 improves mitochondrial biogenesis and function, and thus represents a promising therapeutic agent for the treatment of MELAS.
Highlights
Mitochondria are essential organelles that generate most of the energy required by the human body in the form of adenosine triphosphate (ATP)
We found that KL1333 treatment of C2C12 and L6 myoblasts increased NAD+ levels via the action of NAD(P)H:quinone oxidoreductase 1 (NQO1), and activated the SIRT1/AMP-activated protein kinase (AMPK)/peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) signaling network, which is involved in mitochondrial biogenesis and function
Since KL1333 induces the activation of the SIRT1/AMPK/PGC1α signaling network through NQO1-mediated oxidation of NADH to NAD+ in C2C12 and L6 myoblasts, we investigated whether KL1333 increases the NAD+/NADH ratio and activates SIRT1, AMPK, and PGC-1α in MELAS fibroblasts
Summary
Mitochondria are essential organelles that generate most of the energy required by the human body in the form of adenosine triphosphate (ATP). Mitochondria play roles in generation of reactive oxygen species (ROS) and control of cell signaling, cell death, and biosynthetic metabolism [1]. Mitochondria have their own DNA (mtDNA), which encodes various proteins constituting the electron transport chain, the critical machinery for ATP production [2]. The effects of mitochondrial diseases may occur in any part of the body, but are observed most frequently in tissues that require large amounts of energy, such as brain, heart, and muscle [3]
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