The mystery of mitochondrial plasticity: <scp>TMBIM5</scp> integrates metabolic state and proteostasis

Ren, Mindong; Schlame, Michael

doi:10.15252/embj.2022111834

The EMBO Journal

2022

DOI: 10.15252/embj.2022111834

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The mystery of mitochondrial plasticity: TMBIM5 integrates metabolic state and proteostasis

Mindong Ren

Michael Schlame

Abstract: How cellular cues alter the mitochondrial proteome and impact the composition of mitochondrial proteins remains poorly understood. In this issue of The EMBO Journal, Patron et al (2022) identify TMBIM5 as an important link between calcium homeostasis, proton motive force, and mitochondrial proteolysis, by which the organelle can modify its protein composition. The results may be crucial for our understanding of the plasticity of mitochondria.

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Structure-Based Function and Regulation of NCX Variants: Updates and Challenges

Khananshvili

2022

IJMS

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The plasma-membrane homeostasis Na+/Ca2+ exchangers (NCXs) mediate Ca2+ extrusion/entry to dynamically shape Ca2+ signaling/in biological systems ranging from bacteria to humans. The NCX gene orthologs, isoforms, and their splice variants are expressed in a tissue-specific manner and exhibit nearly 104-fold differences in the transport rates and regulatory specificities to match the cell-specific requirements. Selective pharmacological targeting of NCX variants could benefit many clinical applications, although this intervention remains challenging, mainly because a full-size structure of eukaryotic NCX is unavailable. The crystal structure of the archaeal NCX_Mj, in conjunction with biophysical, computational, and functional analyses, provided a breakthrough in resolving the ion transport mechanisms. However, NCX_Mj (whose size is nearly three times smaller than that of mammalian NCXs) cannot serve as a structure-dynamic model for imitating high transport rates and regulatory modules possessed by eukaryotic NCXs. The crystal structures of isolated regulatory domains (obtained from eukaryotic NCXs) and their biophysical analyses by SAXS, NMR, FRET, and HDX-MS approaches revealed structure-based variances of regulatory modules. Despite these achievements, it remains unclear how multi-domain interactions can decode and integrate diverse allosteric signals, thereby yielding distinct regulatory outcomes in a given ortholog/isoform/splice variant. This article summarizes the relevant issues from the perspective of future developments.

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Structure-Based Function and Regulation of NCX Variants: Updates and Challenges

Khananshvili

2022

IJMS

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The mystery of mitochondrial plasticity: TMBIM5 integrates metabolic state and proteostasis

Cited by 1 publication

References 10 publications

Structure-Based Function and Regulation of NCX Variants: Updates and Challenges

Structure-Based Function and Regulation of NCX Variants: Updates and Challenges

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