bims-cytox1 2020-06-21 papers

Issue of 2020–06–21
two papers selected by
Gavin McStay, Staffordshire University

Proc Natl Acad Sci U S A. 2020 Jun 17. pii: 202002250. [Epub ahead of print]

Mitochondrial protein interaction landscape of SS-31.

Juan D Chavez, Xiaoting Tang, Matthew D Campbell, Gustavo Reyes, Philip A Kramer, Rudy Stuppard, Andrew Keller, Huiliang Zhang, Peter S Rabinovitch, David J Marcinek, James E Bruce.

Mitochondrial dysfunction underlies the etiology of a broad spectrum of diseases including heart disease, cancer, neurodegenerative diseases, and the general aging process. Therapeutics that restore healthy mitochondrial function hold promise for treatment of these conditions. The synthetic tetrapeptide, elamipretide (SS-31), improves mitochondrial function, but mechanistic details of its pharmacological effects are unknown. Reportedly, SS-31 primarily interacts with the phospholipid cardiolipin in the inner mitochondrial membrane. Here we utilize chemical cross-linking with mass spectrometry to identify protein interactors of SS-31 in mitochondria. The SS-31-interacting proteins, all known cardiolipin binders, fall into two groups, those involved in ATP production through the oxidative phosphorylation pathway and those involved in 2-oxoglutarate metabolic processes. Residues cross-linked with SS-31 reveal binding regions that in many cases, are proximal to cardiolipin-protein interacting regions. These results offer a glimpse of the protein interaction landscape of SS-31 and provide mechanistic insight relevant to SS-31 mitochondrial therapy.

Keywords: aging; cross-linking; interactome; mitochondria

DOI: https://doi.org/10.1073/pnas.2002250117

J Life Sci (Westlake Village). 2020 Jun;2(2):

Mitochondrial respiratory chain composition and organization in response to changing oxygen levels.

Alba Timón-Gómez, Antoni Barrientos.

Mitochondria are the major consumer of oxygen in eukaryotic cells, owing to the requirement of oxygen to generate ATP through the mitochondrial respiratory chain (MRC) and the oxidative phosphorylation system (OXPHOS). This aerobic energy transduction is more efficient than anaerobic processes such as glycolysis. Hypoxia, a condition in which environmental or intracellular oxygen levels are below the standard range, triggers an adaptive signaling pathway within the cell. When oxygen concentrations are low, hypoxia-inducible factors (HIFs) become stabilized and activated to mount a transcriptional response that triggers modulation of cellular metabolism to adjust to hypoxic conditions. Mitochondrial aerobic metabolism is one of the main targets of the hypoxic response to regulate its functioning and efficiency in the presence of decreased oxygen levels. During evolution, eukaryotic cells and tissues have increased the plasticity of their mitochondrial OXPHOS system to cope with metabolic needs in different oxygen contexts. In mammalian mitochondria, two factors contribute to this plasticity. First, several subunits of the multimeric MRC complexes I and IV exist in multiple tissue-specific and condition-specific isoforms. Second, the MRC enzymes can coexist organized as individual entities or forming supramolecular structures known as supercomplexes, perhaps in a dynamic manner to respond to environmental conditions and cellular metabolic demands. In this review, we will summarize the information currently available on oxygen-related changes in MRC composition and organization and will discuss gaps of knowledge and research opportunities in the field.

Keywords: Hypoxia; MRC; Mitochondrial OXPHOS; hypoxia-inducible factors (HIFs)

DOI: https://doi.org/10.36069/JoLS/20200601