Malic enzyme 2 maintains protein stability of mutant p53 through 2-hydroxyglutarate.

Many types of cancer feature TP53 mutations with oncogenic properties. However, whether the oncogenic activity of mutant p53 is affected by the cellular metabolic state is unknown. Here we show that cancer-associated mutant p53 protein is stabilized by 2-hydroxyglutarate generated by malic enzyme 2. Mechanistically, malic enzyme 2 promotes the production of 2-hydroxyglutarate by adjusting glutaminolysis, as well as through a reaction that requires pyruvate and NADPH. Malic enzyme 2 depletion decreases cellular 2-hydroxyglutarate levels in vitro and in vivo, whereas elevated malic enzyme 2 expression increases 2-hydroxyglutarate production. We further show that 2-hydroxyglutarate binds directly to mutant p53, which reduces Mdm2-mediated mutant p53 ubiquitination and degradation. 2-Hydroxyglutarate supplementation is sufficient for maintaining mutant p53 protein stability in malic enzyme 2-depleted cells, and restores tumour growth of malic enzyme 2-ablated cells, but not of cells that lack mutant p53. Our findings reveal the previously unrecognized versatility of malic enzyme 2 catalytic functions, and uncover a role for mutant p53 in sensing cellular 2-hydroxyglutarate levels, which contribute to the stabilization of mutant p53 and tumour growth.

Deciphering the roles of caveolin in neurodegenerative diseases: The good, the bad and the importance of context.

Neurodegenerative diseases (NDDs), which contribute to progressive and irreversible impairments of both the structure and function of the nervous system, pose a substantial socioeconomic burden on society. Mitochondrial dysfunction, oxidative stress, membrane damage, DNA damage, and abnormal protein degradation pathways play pivotal roles in the etiology of NDDs. Recently, growing evidence has demonstrated that caveolins are important in the pathology of NDDs due to their cellular functions in signal transduction, endocytosis, transcytosis, cholesterol transport, and lipid homeostasis. Given the significance of caveolins, here we review the literature to clarify their molecular mechanisms and roles in NDDs. We first briefly introduce the general background on caveolins. Next, we focus on the various important functions of caveolins in the brain. Finally, we emphasize recent progress regarding caveolins, especially Cav-1, which exert both benefit and unfavorable effects in NDDs such as AD and PD. Collectively, the data presented here should advance the investigation of caveolins for the future development of innovative strategies for the treatment of NDDs.