Cytosolic malate dehydrogenase activity helps support glycolysis in actively proliferating cells and cancer

Abstract

Increased glucose consumption is a hallmark of cancer cells. The increased consumption and subsequent metabolism of glucose during proliferation creates the need for a constant supply of NAD, a co-factor in glycolysis. Regeneration of the NAD required to support enhanced glycolysis has been attributed to the terminal glycolytic enzyme, lactate dehydrogenase (LDH). However, loss of glucose carbons to biosynthetic pathways early in glycolysis reduces the carbon supply to LDH. Thus, alternative routes for NAD regeneration must exist to support the increased glycolytic rate while allowing for the diversion of glucose to generate biomass and support proliferation. Here we demonstrate, using a variety of cancer cell lines as well as activated primary T cells, that cytosolic malate dehydrogenase 1 (MDH1) is an alternative to LDH as a supplier of NAD. Moreover, our results indicate that MDH1 generates malate with carbons derived from glutamine, thus enabling utilization of glucose carbons for glycolysis and for biomass. Amplification of MDH1 occurs at an impressive frequency in human tumors and correlates with poor prognosis. Together, our findings suggest proliferating cells rely on both MDH1 and LDH to replenish cytosolic NAD and therapies designed at targeting glycolysis must consider both dehydrogenases.

Oxaloacetate Protects Rat Liver From Experimental Warm Ischemia/Reperfusion Injury by Improving Cellular Energy Metabolism

“…In the cytosol, the reduction of OAA to malate oxidizes NADH to NAD+, which stimulates the glycolytic flux . Malate can also provide carbon skeletons to the mitochondria for energy generation.…”

“…In the cytosol, the reduction of OAA to malate oxidizes NADH to NAD+, which stimulates the glycolytic flux. (33,34) Malate can also provide carbon skeletons to the mitochondria for energy generation. Under hypoxic conditions, malate dehydrogenase activity and oxidation of malate to OAA is markedly decreased with the malate to OAA ratio rising from 75-90 to 10,000.…”

T1ρ-weighted Dynamic Glucose-enhanced MR Imaging in the Human Brain

“…lucose metabolism provides the energy for physiologic brain function, and altered glucose supply is associated with several diseases. Increased glucose consumption is a hallmark of cancer cells (1). During the past 3 decades, positron emission tomography (PET) with fluorine 18 ( 18 F) fluorodeoxyglucose has proven its utility as an important clinical tool for diagnosis, staging, and therapy monitoring of multiple cancer types through the visualization of increased tissue glucose uptake and metabolism (2,3).…”

Conversion of a soluble protein into a potent chaperonein vivo

“…We additionally compared the solubility-enhancing effects of RS-mTEV with the representative chaperones for different substrate proteins, including human endostatin, granulocyte colony stimulating factor (GCSF), AP-1 complex subunit mu-2 (Ap1m2), and malate dehydrogenase (hMDH) with the “L” tag at their N-termini. These aggregation-prone proteins have been known to be involved in cell proliferation or signaling pathways [44–47]. Upon individual co-expression of RS, RS-mTEV, GroEL/ES, DnaKJE, and TF, the corresponding solubility were 5%, 47%, 14%, 28%, and 11% for endostatin; 44%, 85%, 53%, 87%, and 94% for GCSF; 7%, 70%, 13%, 36%, and 32% for Ap1m2; and 22%, 79%, 50%, 52%, and 39% for hMDH, respectively ( Fig 4a and c ).…”