bims-smemid 2024-04-07 papers

on Stress metabolism in mitochondrial dysfunction

Issue of 2024–04–07
eight papers selected by
Deepti Mudartha, The International Institute of Molecular Mechanisms and Machines

The energetics of cellular life transitions.
Cytosolic retention of HtrA2 during mitochondrial protein import stress triggers the DELE1-HRI pathway.
The Odds of Protein Translation Control under Stress.
Long-range electron proton coupling in respiratory complex I - insights from molecular simulations of the quinone chamber and antiporter-like subunits.
Soluble klotho induces the heat shock factor 1 through EGR1 expression.
Oncogenic Control of Metabolism.
Targeting reprogrammed metabolism as a therapeutic approach for respiratory diseases.
The ER-SURF pathway uses ER-mitochondria contact sites for protein targeting to mitochondria.

Life Metab. 2024 Jun;pii: load051. [Epub ahead of print]3(3):

The energetics of cellular life transitions.

Anna S Monzel, Michael Levin, Martin Picard.

  Major life transitions are always difficult because change costs energy. Recent findings have demonstrated how mitochondrial oxidative phosphorylation (OxPhos) defects increase the energetic cost of living, and that excessive integrated stress response (ISR) signaling may prevent cellular identity transitions during development. In this perspective, we discuss general bioenergetic principles of life transitions and the costly molecular processes involved in reprograming the cellular hardware/software as cells shift identity. The energetic cost of cellular differentiation has not been directly quantified, representing a gap in knowledge. We propose that the ISR is an energetic checkpoint evolved to i) prevent OxPhos-deficient cells from engaging in excessively costly transitions, and ii) allow ISR-positive cells to recruit systemic energetic resources by signaling via the brain.

Keywords:  GDF15; development; energy; energy balance; mitochondria; signaling pathway

DOI:  https://doi.org/10.1093/lifemeta/load051
Commun Biol. 2024 Mar 30. 7(1): 391

Cytosolic retention of HtrA2 during mitochondrial protein import stress triggers the DELE1-HRI pathway.

Paul Y Bi, Samuel A Killackey, Linus Schweizer, Damien Arnoult, Dana J Philpott, Stephen E Girardin.

Mitochondrial stress inducers such as carbonyl cyanide m-chlorophenyl hydrazone (CCCP) and oligomycin trigger the DELE1-HRI branch of the integrated stress response (ISR) pathway. Previous studies performed using epitope-tagged DELE1 showed that these stresses induced the cleavage of DELE1 to DELE1-S, which stimulates HRI. Here, we report that mitochondrial protein import stress (MPIS) is an overarching stress that triggers the DELE1-HRI pathway, and that endogenous DELE1 could be cleaved into two forms, DELE1-S and DELE1-VS, the latter accumulating only upon non-depolarizing MPIS. Surprisingly, while the mitochondrial protease OMA1 was crucial for DELE1 cleavage in HeLa cells, it was dispensable in HEK293T cells, suggesting that multiple proteases may be involved in DELE1 cleavage. In support, we identified a role for the mitochondrial protease, HtrA2, in mediating DELE1 cleavage into DELE1-VS, and showed that a Parkinson's disease (PD)-associated HtrA2 mutant displayed reduced DELE1 processing ability, suggesting a novel mechanism linking PD pathogenesis to mitochondrial stress. Our data further suggest that DELE1 is likely cleaved into DELE1-S in the cytosol, while the DELE1-VS form might be generated during halted translocation into mitochondria. Together, this study identifies MPIS as the overarching stress detected by DELE1 and identifies a novel role for HtrA2 in DELE1 processing.

DOI: https://doi.org/10.1038/s42003-024-06107-7
Antioxid Redox Signal. 2024 Apr 04.

The Odds of Protein Translation Control under Stress.

Qin Chen.

Physical or chemical stress is commonly known to inhibit protein translation at the cellular level. Since the process of protein translation requires catalysis by a multi-component machinery containing eIFs and ribosomes in a sequence of reactions, how the process fails to proceed and whether certain genes can escape such blockade have provoked research efforts. Lines of evidence have demonstrated that phosphorylation of eIF4E or dephosphorylation of 4E-BPs prevents formation of the eIF4F complex, whereas phosphorylation of eIF2α due to activation of HRI, GCN2, PERK or PKR by a diverse array of stressors prevents eIF2-GTP-tRNAiMet ternary complex assembly. These signal the abandonment of translation initiation via 5' 7-methylguanine (m7G) cap recognition by eIF4E. Stress can promote cleavage of tRNAs, impediment of rRNA processing, changes in the epitranscriptomic landscape, ribosome stalling or collision, activation of ribosomal surveillance systems, and assembly of the stress granules. Although these events contribute to general inhibition of protein translation, a few proteins can bypass such negativity and become translated selectively. Such selective protein translation is primarily m7G cap independent through the integrated stress response or Internal Ribosomal Entry Site (IRES). The newly synthesized proteins often influence cell fate, facilitate cell survival and build endogenous defense. Insights into general inhibition of protein translation and selective translation of specific proteins will advance our understanding of the etiology or progression of human diseases involving cellular stress from viral infection or inflammation to myocardial infarction, stroke or neurodegenerative disease.

DOI: https://doi.org/10.1089/ars.2023.0478
Biochem J. 2024 Apr 10. 481(7): 499-514

Long-range electron proton coupling in respiratory complex I - insights from molecular simulations of the quinone chamber and antiporter-like subunits.

Amina Djurabekova, Jonathan Lasham, Oleksii Zdorevskyi, Volker Zickermann, Vivek Sharma.

  Respiratory complex I is a redox-driven proton pump. Several high-resolution structures of complex I have been determined providing important information about the putative proton transfer paths and conformational transitions that may occur during catalysis. However, how redox energy is coupled to the pumping of protons remains unclear. In this article, we review biochemical, structural and molecular simulation data on complex I and discuss several coupling models, including the key unresolved mechanistic questions. Focusing both on the quinone-reductase domain as well as the proton-pumping membrane-bound domain of complex I, we discuss a molecular mechanism of proton pumping that satisfies most experimental and theoretical constraints. We suggest that protonation reactions play an important role not only in catalysis, but also in the physiologically-relevant active/deactive transition of complex I.

Keywords:  MD simulations; energy conversion; mitochondrial respiration; protein dynamics; proton pump

DOI:  https://doi.org/10.1042/BCJ20240009
Biofactors. 2024 Apr 04.

Soluble klotho induces the heat shock factor 1 through EGR1 expression.

Soo-A Kim, Nguyen Khanh Toan, Sang-Gun Ahn.

  Klotho is an antiaging protein that has multiple functions. The purpose of this study is to investigate whether soluble klotho plays a role in cellular stress response pathways. We found that klotho deficiency (kl-/-) largely decreased HSF1 levels and impaired heat shock protein expression. Interestingly, recombinant soluble klotho-induced HSF1 and HSPs such as HSP90, HSP70, and HSP27 in kl-/- mouse embryonic fibroblasts (MEFs). Soluble Klotho treatment also induced cell proliferation and HSF1 promoter activity in MEF kl-/- cells in a concentration-dependent manner. Furthermore, using point mutagenesis, we identified regulatory/binding sites of transcription factors EGR1 regulated by soluble klotho in the HSF1 promoter. Taken together, our findings unravel the molecular basis of klotho and provide molecular evidence supporting a direct interaction between soluble klotho and HSF1-mediated stress response pathway.

Keywords:  EGR1; HSF1; HSPs; anti‐aging; klotho

DOI:  https://doi.org/10.1002/biof.2056
Cold Spring Harb Perspect Med. 2024 Apr 02. pii: a041531. [Epub ahead of print]

Oncogenic Control of Metabolism.

Natalya N Pavlova, Craig B Thompson.

A cell committed to proliferation must reshape its metabolism to enable robust yet balanced production of building blocks for the assembly of proteins, lipids, nucleic acids, and other macromolecules, from which two functional daughter cells can be produced. The metabolic remodeling associated with proliferation is orchestrated by a number of pro-proliferative signaling nodes, which include phosphatidylinositol-3 kinase (PI3K), the RAS family of small GTPases, and transcription factor c-myc In metazoan cells, these signals are activated in a paracrine manner via growth factor-mediated activation of receptor (or receptor-associated) tyrosine kinases. Such stimuli are limited in duration and therefore allow the metabolism of target cells to return to the resting state once the proliferation demands have been satisfied. Cancer cells acquire activating genetic alterations within common pro-proliferative signaling nodes. These alterations lock cellular nutrient uptake and utilization into a perpetual progrowth state, leading to the aberrant accumulation and spread of cancer cells.

DOI: https://doi.org/10.1101/cshperspect.a041531
Biochem Pharmacol. 2024 Mar 30. pii: S0006-2952(24)00170-9. [Epub ahead of print] 116187

Targeting reprogrammed metabolism as a therapeutic approach for respiratory diseases.

Phyllis X L Gan, Shanshan Zhang, W S Fred Wong.

  Metabolic reprogramming underlies the etiology and pathophysiology of respiratory diseases such as asthma, idiopathic pulmonary fibrosis (IPF), and chronic obstructive pulmonary disease (COPD). The dysregulated cellular activities driving airway inflammation and remodelling in these diseases have reportedly been linked to aberrant shifts in energy-producing metabolic pathways: glycolysis and oxidative phosphorylation (OXPHOS). The rewiring of glycolysis and OXPHOS accompanying the therapeutic effects of many clinical compounds and natural products in asthma, IPF, and COPD, supports targeting metabolism as a therapeutic approach for respiratory diseases. Correspondingly, inhibiting glycolysis has largely attested effective against experimental asthma, IPF, and COPD. However, modulating OXPHOS and its supporting catabolic pathways like mitochondrial pyruvate catabolism, fatty acid β-oxidation (FAO), and glutaminolysis for these respiratory diseases remain inconclusive. An emerging repertoire of metabolic enzymes are also interconnected to these canonical metabolic pathways that similarly possess therapeutic potential for respiratory diseases. Taken together, this review highlights the urgent demand for future studies to ascertain the role of OXPHOS in different respiratory diseases, under different stimulatory conditions, and in different cell types. While this review provides strong experimental evidence in support of the inhibition of glycolysis for asthma, IPF, and COPD, further verification by clinical trials is definitely required.

Keywords:  Asthma; Chronic obstructive pulmonary disease; Glycolysis; Idiopathic pulmonary fibrosis; Oxidative phosphorylation

DOI:  https://doi.org/10.1016/j.bcp.2024.116187
EMBO Rep. 2024 Apr 02.

The ER-SURF pathway uses ER-mitochondria contact sites for protein targeting to mitochondria.

Christian Koch, Svenja Lenhard, Markus Räschle, Cristina Prescianotto-Baschong, Anne Spang, Johannes M Herrmann.

  Most mitochondrial proteins are synthesized on cytosolic ribosomes and imported into mitochondria in a post-translational reaction. Mitochondrial precursor proteins which use the ER-SURF pathway employ the surface of the endoplasmic reticulum (ER) as an important sorting platform. How they reach the mitochondrial import machinery from the ER is not known. Here we show that mitochondrial contact sites play a crucial role in the ER-to-mitochondria transfer of precursor proteins. The ER mitochondria encounter structure (ERMES) and Tom70, together with Djp1 and Lam6, are part of two parallel and partially redundant ER-to-mitochondria delivery routes. When ER-to-mitochondria transfer is prevented by loss of these two contact sites, many precursors of mitochondrial inner membrane proteins are left stranded on the ER membrane, resulting in mitochondrial dysfunction. Our observations support an active role of the ER in mitochondrial protein biogenesis.

Keywords:  Contact sites; ERMES; Endoplasmic reticulum; Mitochondria; Protein import

DOI:  https://doi.org/10.1038/s44319-024-00113-w