bims-resufa 2020-10-11 papers

Issue of 2020–10–11
two papers selected by
Vera Strogolova, Marquette University

EMBO Rep. 2020 Oct 05. e51015

Respiratory supercomplexes enhance electron transport by decreasing cytochrome c diffusion distance.

Jens Berndtsson, Andreas Aufschnaiter, Sorbhi Rathore, Lorena Marin-Buera, Hannah Dawitz, Jutta Diessl, Verena Kohler, Antoni Barrientos, Sabrina Büttner, Flavia Fontanesi, Martin Ott.

Respiratory chains are crucial for cellular energy conversion and consist of multi-subunit complexes that can assemble into supercomplexes. These structures have been intensively characterized in various organisms, but their physiological roles remain unclear. Here, we elucidate their function by leveraging a high-resolution structural model of yeast respiratory supercomplexes that allowed us to inhibit supercomplex formation by mutation of key residues in the interaction interface. Analyses of a mutant defective in supercomplex formation, which still contains fully functional individual complexes, show that the lack of supercomplex assembly delays the diffusion of cytochrome c between the separated complexes, thus reducing electron transfer efficiency. Consequently, competitive cellular fitness is severely reduced in the absence of supercomplex formation and can be restored by overexpression of cytochrome c. In sum, our results establish how respiratory supercomplexes increase the efficiency of cellular energy conversion, thereby providing an evolutionary advantage for aerobic organisms.

Keywords: bioenergetics; competitive fitness; cryo-EM; mitochondria; respiratory chain supercomplexes

DOI: https://doi.org/10.15252/embr.202051015

Cell Rep. 2020 Oct 06. pii: S2211-1247(20)31220-1. [Epub ahead of print]33(1): 108231

Respiratory Supercomplexes Promote Mitochondrial Efficiency and Growth in Severely Hypoxic Pancreatic Cancer.

Kate E R Hollinshead, Seth J Parker, Vinay V Eapen, Joel Encarnacion-Rosado, Albert Sohn, Tugba Oncu, Michael Cammer, Joseph D Mancias, Alec C Kimmelman.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by extensive fibrosis and hypovascularization, resulting in significant intratumoral hypoxia (low oxygen) that contributes to its aggressiveness, therapeutic resistance, and high mortality. Despite oxygen being a fundamental requirement for many cellular and metabolic processes, and the severity of hypoxia in PDAC, the impact of oxygen deprivation on PDAC biology is poorly understood. Investigating how PDAC cells survive in the near absence of oxygen, we find that PDAC cell lines grow robustly in oxygen tensions down to 0.1%, maintaining mitochondrial morphology, membrane potential, and the oxidative metabolic activity required for the synthesis of key metabolites for proliferation. Disrupting electron transfer efficiency by targeting mitochondrial respiratory supercomplex assembly specifically affects hypoxic PDAC proliferation, metabolism, and in vivo tumor growth. Collectively, our results identify a mechanism that enables PDAC cells to thrive in severe, oxygen-limited microenvironments.

Keywords: COX7A2L; aspartate; electron transport chain; hypoxia; pancreatic cancer; respiration; supercomplexes

DOI: https://doi.org/10.1016/j.celrep.2020.108231