bims-mitdyn 2024-09-29 papers

bims-mitdyn

Biomed News

on Mitochondrial dynamics: mechanisms

Issue of 2024–09–29
ten papers selected by
Edmond Chan, Queen’s University, School of Medicine

Mitochondrial protein heterogeneity stems from the stochastic nature of co-translational protein targeting in cell senescence.
Mitochondria-targeted cancer analysis using survival and expression: Prioritizing mitochondrial targets that alleviate pancreatic cancer cell phenotypes.
Macrophage NRF1 promotes mitochondrial protein turnover via the ubiquitin proteasome system to limit mitochondrial stress and inflammation.
The deubiquitinase Ubp3/Usp10 constrains glucose-mediated mitochondrial repression via phosphate budgeting.
Mitochondrial membrane potential and oxidative stress interact to regulate Oma1-dependent processing of Opa1 and mitochondrial dynamics.
Geranylgeranylated SCFFBXO10 regulates selective outer mitochondrial membrane proteostasis and function.
Protocol to monitor live-cell, real-time, mitochondrial respiration in mouse muscle cells using the Resipher platform.
A transmitochondrial sodium gradient controls membrane potential in mammalian mitochondria.
Quality control of mitochondria involves lysosomes in multiple definitive ways.
Multivariate analysis of metabolic state vulnerabilities across diverse cancer contexts reveals synthetically lethal associations.

Nat Commun. 2024 Sep 27. 15(1): 8274

Mitochondrial protein heterogeneity stems from the stochastic nature of co-translational protein targeting in cell senescence.

Abdul Haseeb Khan, Xuefang Gu, Rutvik J Patel, Prabha Chuphal, Matheus P Viana, Aidan I Brown, Brian M Zid, Tatsuhisa Tsuboi.

A decline in mitochondrial function is a hallmark of aging and neurodegenerative diseases. It has been proposed that changes in mitochondrial morphology, including fragmentation of the tubular mitochondrial network, can lead to mitochondrial dysfunction, yet the mechanism of this loss of function is unclear. Most proteins contained within mitochondria are nuclear-encoded and must be properly targeted to the mitochondria. Here, we report that sustained mRNA localization and co-translational protein delivery leads to a heterogeneous protein distribution across fragmented mitochondria. We find that age-induced mitochondrial fragmentation drives a substantial increase in protein expression noise across fragments. Using a translational kinetic and molecular diffusion model, we find that protein expression noise is explained by the nature of stochastic compartmentalization and that co-translational protein delivery is the main contributor to increased heterogeneity. We observed that cells primarily reduce the variability in protein distribution by utilizing mitochondrial fission-fusion processes rather than relying on the mitophagy pathway. Furthermore, we are able to reduce the heterogeneity of the protein distribution by inhibiting co-translational protein targeting. This research lays the framework for a better understanding of the detrimental impact of mitochondrial fragmentation on the physiology of cells in aging and disease.

DOI: https://doi.org/10.1038/s41467-024-52183-y
iScience. 2024 Sep 20. 27(9): 110880

Mitochondria-targeted cancer analysis using survival and expression: Prioritizing mitochondrial targets that alleviate pancreatic cancer cell phenotypes.

Daisuke Murata, Fumiya Ito, Gongyu Tang, Wakiko Iwata, Nelson Yeung, Junior J West, Andrew J Ewald, Xiaowei Wang, Miho Iijima, Hiromi Sesaki.

  Substantial changes in energy metabolism are a hallmark of pancreatic cancer. To adapt to hypoxic and nutrient-deprived microenvironments, pancreatic cancer cells remodel their bioenergetics from oxidative phosphorylation to glycolysis. This bioenergetic shift makes mitochondria an Achilles' heel. Since mitochondrial function remains essential for pancreatic cancer cells, further depleting mitochondrial energy production is an appealing treatment target. However, identifying effective mitochondrial targets for treatment is challenging. Here, we developed an approach, mitochondria-targeted cancer analysis using survival and expression (mCAUSE), to prioritize target proteins from the entire mitochondrial proteome. Selected proteins were further tested for their impact on pancreatic cancer cell phenotypes. We discovered that targeting a dynamin-related GTPase, OPA1, which controls mitochondrial fusion and cristae, effectively suppresses pancreatic cancer activities. Remarkably, when combined with a mutation-specific KRAS inhibitor, OPA1 inhibition showed a synergistic effect. Our findings offer a therapeutic strategy against pancreatic cancer by simultaneously targeting mitochondria dynamics and KRAS signaling.

Keywords:  Cancer; Cell biology; Molecular biology

DOI:  https://doi.org/10.1016/j.isci.2024.110880
Cell Rep. 2024 Sep 25. pii: S2211-1247(24)01131-8. [Epub ahead of print]43(10): 114780

Macrophage NRF1 promotes mitochondrial protein turnover via the ubiquitin proteasome system to limit mitochondrial stress and inflammation.

Jiawei Yan, Xin Zhang, Huiying Wang, Xinglong Jia, Ruohong Wang, Shuangyang Wu, Zheng-Jiang Zhu, Minjia Tan, Tiffany Horng.

  Macrophage elaboration of inflammatory responses is dynamically regulated, shifting from acute induction to delayed suppression during the course of infection. Here, we show that such regulation of inflammation is modulated by dynamic shifts in metabolism. In macrophages exposed to the bacterial product lipopolysaccharide (LPS), an initial induction of protein biosynthesis is followed by compensatory induction of the transcription factor nuclear factor erythroid 2-like 1 (NRF1), leading to increased flux through the ubiquitin proteasome system (UPS). A major target of NRF1-mediated UPS flux is the mitochondrial proteome, and in the absence of NRF1, ubiquitinated mitochondrial proteins accumulate to trigger severe mitochondrial stress. Such mitochondrial stress engages the integrated stress response-ATF4 axis, which limits mitochondrial translation to attenuate mitochondrial stress but amplifies inflammatory responses to augment susceptibility to septic shock. Therefore, NRF1 mediates a dynamic regulation of mitochondrial proteostasis in inflammatory macrophages that contributes to curbing inflammatory responses.

Keywords:  CP: Metabolism; CP: Molecular biology; NRF1; immunometabolism; inflammation; integrated stress response; macrophage; mitochondria; proteostasis

DOI:  https://doi.org/10.1016/j.celrep.2024.114780
Elife. 2024 Sep 26. pii: RP90293. [Epub ahead of print]12

The deubiquitinase Ubp3/Usp10 constrains glucose-mediated mitochondrial repression via phosphate budgeting.

Vineeth Vengayil, Shreyas Niphadkar, Swagata Adhikary, Sriram Varahan, Sunil Laxman.

  Many cells in high glucose repress mitochondrial respiration, as observed in the Crabtree and Warburg effects. Our understanding of biochemical constraints for mitochondrial activation is limited. Using a Saccharomyces cerevisiae screen, we identified the conserved deubiquitinase Ubp3 (Usp10), as necessary for mitochondrial repression. Ubp3 mutants have increased mitochondrial activity despite abundant glucose, along with decreased glycolytic enzymes, and a rewired glucose metabolic network with increased trehalose production. Utilizing ∆ubp3 cells, along with orthogonal approaches, we establish that the high glycolytic flux in glucose continuously consumes free Pi. This restricts mitochondrial access to inorganic phosphate (Pi), and prevents mitochondrial activation. Contrastingly, rewired glucose metabolism with enhanced trehalose production and reduced GAPDH (as in ∆ubp3 cells) restores Pi. This collectively results in increased mitochondrial Pi and derepression, while restricting mitochondrial Pi transport prevents activation. We therefore suggest that glycolytic flux-dependent intracellular Pi budgeting is a key constraint for mitochondrial repression.

Keywords:  GAPDH; S. cerevisiae; biochemistry; cancer biology; chemical biology; glycolysis; inorganic phosphate; metabolic flux; mitochondria; trehalose

DOI:  https://doi.org/10.7554/eLife.90293
FASEB J. 2024 Sep 30. 38(18): e70066

Mitochondrial membrane potential and oxidative stress interact to regulate Oma1-dependent processing of Opa1 and mitochondrial dynamics.

Garrett M Fogo, Sarita Raghunayakula, Katlynn J Emaus, Francisco J Torres Torres, Joseph M Wider, Thomas H Sanderson.

  Mitochondrial form and function are regulated by the opposing forces of mitochondrial dynamics: fission and fusion. Mitochondrial dynamics are highly active and consequential during neuronal ischemia/reperfusion (I/R) injury. Mitochondrial fusion is executed at the mitochondrial inner membrane by Opa1. The balance of long (L-Opa1) and proteolytically cleaved short (S-Opa1) isoforms is critical for efficient fusion. Oma1 is the predominant stress-responsive protease for Opa1 processing. In neuronal cell models, we assessed Oma1 and Opa1 regulation during mitochondrial stress. In an immortalized mouse hippocampal neuron line (HT22), Oma1 was sensitive to mitochondrial membrane potential depolarization (rotenone, FCCP) and hyperpolarization (oligomycin). Further, oxidative stress was sufficient to increase Oma1 activity and necessary for depolarization-induced proteolysis. We generated Oma1 knockout (KO) HT22 cells that displayed normal mitochondrial morphology and fusion capabilities. FCCP-induced mitochondrial fragmentation was exacerbated in Oma1 KO cells. However, Oma1 KO cells were better equipped to perform restorative fusion after fragmentation, presumably due to preserved L-Opa1. We extended our investigations to a combinatorial stress of neuronal oxygen-glucose deprivation and reoxygenation (OGD/R), where we found that Opa1 processing and Oma1 activation were initiated during OGD in an ROS-dependent manner. These findings highlight a novel dependence of Oma1 on oxidative stress in response to depolarization. Further, we demonstrate contrasting fission/fusion roles for Oma1 in the acute response and recovery stages of mitochondrial stress. Collectively, our results add intersectionality and nuance to the previously proposed models of Oma1 activity.

Keywords:  membrane fusion; membrane potential; mitochondria; mitochondrial dynamics; proteostasis; reactive oxygen species

DOI:  https://doi.org/10.1096/fj.202400313R
Cell Rep. 2024 Sep 21. pii: S2211-1247(24)01134-3. [Epub ahead of print]43(10): 114783

Geranylgeranylated SCFFBXO10 regulates selective outer mitochondrial membrane proteostasis and function.

Sameer Ahmed Bhat, Zahra Vasi, Liping Jiang, Shruthi Selvaraj, Rachel Ferguson, Sanaz Salarvand, Anish Gudur, Ritika Adhikari, Veronica Castillo, Hagar Ismail, Avantika Dhabaria, Beatrix Ueberheide, Shafi Kuchay.

  Compartment-specific cellular membrane protein turnover is not well understood. We show that FBXO10, the interchangeable component of the cullin-RING-ligase 1 complex, undergoes lipid modification with geranylgeranyl isoprenoid at cysteine953, facilitating its dynamic trafficking to the outer mitochondrial membrane (OMM). FBXO10 polypeptide lacks a canonical mitochondrial targeting sequence (MTS); instead, its geranylgeranylation at C953 and interaction with two cytosolic factors, cytosolic factor-like δ subunit of type 6 phosphodiesterase (PDE6δ; a prenyl-group-binding protein) and heat shock protein 90 (HSP90; a chaperone), orchestrate specific OMM targeting of prenyl-FBXO10. The FBXO10(C953S) mutant redistributes away from the OMM, impairs mitochondrial ATP production and membrane potential, and increases fragmentation. Phosphoglycerate mutase-5 (PGAM5) was identified as a potential substrate of FBXO10 at the OMM using comparative quantitative proteomics of enriched mitochondria. FBXO10 loss or expression of prenylation-deficient FBXO10(C953S) inhibited PGAM5 degradation, disrupted mitochondrial homeostasis, and impaired myogenic differentiation of human induced pluripotent stem cells (iPSCs) and murine myoblasts. Our studies identify a mechanism for FBXO10-mediated regulation of selective mitochondrial proteostasis potentially amenable to therapeutic intervention.

Keywords:  CP: Metabolism; CP: Molecular biology; E3-ligase; F-box protein; FBXO10; HSP90; PDE6δ; mitochondria; prenylation; trafficking; ubiquitination

DOI:  https://doi.org/10.1016/j.celrep.2024.114783
STAR Protoc. 2024 Sep 20. pii: S2666-1667(24)00495-7. [Epub ahead of print]5(4): 103330

Protocol to monitor live-cell, real-time, mitochondrial respiration in mouse muscle cells using the Resipher platform.

Matthew Triolo, Mireille Khacho.

  Mitochondrial function is typically assessed by measuring oxygen consumption at a given time point. However, this approach cannot monitor respiratory changes that occur over time. Here, we present a protocol to measure mitochondrial respiration in freshly isolated muscle stem cells, primary skeletal muscle, and immortalized C2C12 myoblasts in real time using the Resipher platform. We describe steps for preparing and plating cells, performing media changes, setting up the software and device, and analyzing data. This method can be adapted to other cell types. For complete details on the use and execution of this protocol, please refer to Triolo et al.1.

Keywords:  Cell Biology; Metabolism; Stem Cells

DOI:  https://doi.org/10.1016/j.xpro.2024.103330
Cell. 2024 Sep 17. pii: S0092-8674(24)00974-7. [Epub ahead of print]

A transmitochondrial sodium gradient controls membrane potential in mammalian mitochondria.

Pablo Hernansanz-Agustín, Carmen Morales-Vidal, Enrique Calvo, Paolo Natale, Yolanda Martí-Mateos, Sara Natalia Jaroszewicz, José Luis Cabrera-Alarcón, Rebeca Acín-Pérez, Iván López-Montero, Jesús Vázquez, José Antonio Enríquez.

  Eukaryotic cell function and survival rely on the use of a mitochondrial H+ electrochemical gradient (Δp), which is composed of an inner mitochondrial membrane (IMM) potential (ΔΨmt) and a pH gradient (ΔpH). So far, ΔΨmt has been assumed to be composed exclusively of H+. Here, using a rainbow of mitochondrial and nuclear genetic models, we have discovered that a Na+ gradient equates with the H+ gradient and controls half of ΔΨmt in coupled-respiring mammalian mitochondria. This parallelism is controlled by the activity of the long-sought Na+-specific Na+/H+ exchanger (mNHE), which we have identified as the P-module of complex I (CI). Deregulation of this mNHE function, without affecting the canonical enzymatic activity or the assembly of CI, occurs in Leber's hereditary optic neuropathy (LHON), which has profound consequences in ΔΨmt and mitochondrial Ca2+ homeostasis and explains the previously unknown molecular pathogenesis of this neurodegenerative disease.

Keywords:  LHON; Na(+) gradient; complex I; mitochondrial Na(+)/H(+) antiporter; ΔΨmt

DOI:  https://doi.org/10.1016/j.cell.2024.08.045
Autophagy. 2024 Sep 26.

Quality control of mitochondria involves lysosomes in multiple definitive ways.

Xiaowen Ma, Wen-Xing Ding.

  Mitochondria are crucial organelles in maintaining cellular homeostasis. They are involved in processes such as energy production, metabolism of lipids and glucose, and cell death regulation. Mitochondrial dysfunction can lead to various health issues such as aging, cancer, neurodegenerative diseases, and chronic liver diseases. While mitophagy is the main process for getting rid of excess or damaged mitochondria, there are additional mechanisms for preserving mitochondrial quality. One such alternative mechanism we have discovered is a hybrid organelle called mitochondrial-lysosome-related-organelle (MLRO), which functions independently of the typical autophagy process. More recently, another type of vesicle called vesicle derived from the inner mitochondrial membrane (VDIM) has been identified to break down the inner mitochondrial membrane without involving the standard autophagy pathway. In this article, we will delve into the similarities and differences between MLRO and VDIM, including their structure, regulation, and relevance to human diseases.

Keywords:  Autophagy; DNM1L/DRP1; MLRO; VDIM; mitophagy

DOI:  https://doi.org/10.1080/15548627.2024.2408712
Cell Rep. 2024 Sep 20. pii: S2211-1247(24)01126-4. [Epub ahead of print]43(10): 114775

Multivariate analysis of metabolic state vulnerabilities across diverse cancer contexts reveals synthetically lethal associations.

Cara Abecunas, Audrey D Kidd, Ying Jiang, Hui Zong, Mohammad Fallahi-Sichani.

  Targeting the distinct metabolic needs of tumor cells has recently emerged as a promising strategy for cancer therapy. The heterogeneous, context-dependent nature of cancer cell metabolism, however, poses challenges to identifying effective therapeutic interventions. Here, we utilize various unsupervised and supervised multivariate modeling approaches to systematically pinpoint recurrent metabolic states within hundreds of cancer cell lines, elucidate their association with tumor lineage and growth environments, and uncover vulnerabilities linked to their metabolic states across diverse genetic and tissue contexts. We validate key findings via analysis of data from patient-derived tumors and pharmacological screens and by performing genetic and pharmacological experiments. Our analysis uncovers synthetically lethal associations between the tumor metabolic state (e.g., oxidative phosphorylation), driver mutations (e.g., loss of tumor suppressor PTEN), and actionable biological targets (e.g., mitochondrial electron transport chain). Investigating the mechanisms underlying these relationships can inform the development of more precise and context-specific, metabolism-targeted cancer therapies.

Keywords:  CP: Cancer; CP: Metabolism; PTEN; cancer metabolism; cancer therapies; glioma; metabolic state vulnerabilities; mitochondrial electron transport chain; multivariate modeling; oxidative phosphorylation; synthetic lethality

DOI:  https://doi.org/10.1016/j.celrep.2024.114775