👤 JK Pullen

Introduction: Drugs targeting mitochondria are emerging as promising antitumor therapeutics in preclinical models. However, a few of these drugs have shown clinical toxicity. Developing mitochondria-targeted modified natural compounds and US FDA-approved drugs with increased therapeutic index in cancer is discussed as an alternative strategy. Areas Covered: Triphenylphosphonium cation (TPP + )-based drugs selectively accumulate in the mitochondria of cancer cells due to their increased negative membrane potential, target the oxidative phosphorylation proteins, inhibit mitochondrial respiration, and inhibit tumor proliferation. TPP + -based drugs exert minimal toxic side effects in rodents and humans. These drugs can sensitize radiation and immunotherapies. Expert Opinion: TPP + -based drugs targeting the tumor mitochondrial electron transport chain are a new class of oxidative phosphorylation inhibitors with varying antiproliferative and antimetastatic potencies. Some of these TPP + -based agents, which are synthesized from naturally occurring molecules and FDA-approved drugs, have been tested in mice and did not show notable toxicity, including neurotoxicity, when used at doses under the maximally tolerated dose. Thus, more effort should be directed toward the clinical translation of TPP + -based OXPHOS-inhibiting drugs in cancer prevention and treatment. Show less

Mitochondrial calcium uptake plays critical roles in regulating ATP production, intracellular calcium signaling, and cell death. This uptake is mediated by a highly selective calcium channel called the mitochondrial calcium uniporter. Here, we determined the structures of the pore-forming MCU proteins by X-ray crystallography and single-particle cryo-electron microscopy. The stoichiometry, overall architecture, and individual subunit structure differed markedly from those in the recent nuclear magnetic resonance structure of the Caenorhabditis elegans MCU. In our studies, we observed a dimer-of-dimer architecture across species and chemical environments, which was corroborated by biochemical experiments. Structural analyses and functional characterizations uncovered the roles of critical residues in the pore. These results reveal a new ion channel architecture, provide insights into calcium coordination, selectivity, and conduction, and establish a structural framework for understanding the mechanism of mitochondrial calcium uniporter function. Show less

Mitochondrial Ca 2+ uptake plays a pivotal role both in cell energy balance and in cell fate determination. Studies on the role of mitochondrial Ca 2+ signaling in pathophysiology have been favored by the identification of the genes encoding the mitochondrial calcium uniporter (MCU) and its regulatory subunits. Thus, research carried on in the last years on one hand has determined the structure of the MCU complex and its regulation, on the other has uncovered the consequences of dysregulated mitochondrial Ca 2+ signaling in cell and tissue homeostasis. Whether mitochondrial Ca 2+ uptake can be exploited as a weapon to counteract cancer progression is debated. In this review, we summarize recent research on the molecular structure of the MCU, the regulatory mechanisms that control its activity and its relevance in pathophysiology, focusing in particular on its role in cancer progression. Show less