Mitochondria is an essential organelle, and it generates most of the energy required by the human body in the form of adenosine triphosphate (ATP).

Additionally, mitochondria play an important role in the generation of ROS. What’s more, this organelle also controls the cell signal, cell death and biosynthetic metabolism. Mitochondria have mtDNA, which encodes various proteins constituting the electron transport chain. Therefore, mutations in any of the mitochondrial genes can result in mitochondrial dysfunction.
NAD⁺ and its reduced form (NADH) are important regulators of many cellular signaling pathways. Besides, NAD⁺ acts as a cofactor for several NAD⁺-consuming enzymes, such as sirtuins, poly(ADP-ribose) polymerases (PARPs), and cyclic ADP-ribose synthases.

mitochondrial dysfunction or aging always leads to decreased intracellular NAD⁺ levels. KL1333 has the potential for mitochondrial diseases treatment, including stroke-like episodes (MELAS). KL1333 has the ability to increase the NAD⁺/NADH ratio in MELAS.

In this article, we will introduce an orally available NAD⁺ modulator, KL1333.

KL1333 is a derivative of β-lapachone. Additionally, this compound reacts with NAD(P)H:quinone oxidoreductase 1 (NQO1) as a substrate. As a result, it leads to increases in intracellular NAD⁺ levels via NADH oxidation.

KL1333 improves energy metabolism and mitochondrial dysfunction in MELAS fibroblasts. What’s more, it protects against cisplatin-induced cytotoxicity in mouse cochlear cultures. AS a potent modulator of the cellular levels of NAD⁺, a central coenzyme in the cell’s energy metabolism. Elevated NAD⁺ levels trigger the activation of SIRT1 and AMPK, and subsequently activate PGC-1α.

Additionally, in db/db mice, activates AMPK and SIRT1 in vivo. KL1333 can activate several transcription factors involved in mitochondrial and metabolic gene expression. And it upregulates the major mitochondrial regulator PGC-1α mediated by SIRT1 and AMPK, respectively. Besides, SIRT1 and AMPK are major metabolic sensors that play various roles in glucose and lipid metabolism.

In conclusion, KL1333 is a potent NAD⁺ modulator and plays an important role in mitochondria-related metabolic diseases.

[1]. Seo KS, et al. Front Neurol. 2018;9:552. Published 2018 Jul 5.

[2]. Lee HS, et al. Biomed Pharmacother. 2020;126:110068.