bims-mikwok 2023-03-19 papers

bims-mikwok

Biomed News

on Mitochondrial quality control

Issue of 2023‒03‒19
twenty-two papers selected by
Avinash N. Mukkala
University of Toronto

Augmented Parkin-dependent mitophagy underlies the hepatoprotective effect of remote ischemic conditioning used prior to hemorrhagic shock.
Exogenous mitochondrial transplantation improves survival and neurological outcomes after resuscitation from cardiac arrest.
Mitochondrial-derived vesicles retain membrane potential and contain a functional ATP synthase.
Omics-based approaches for the systematic profiling of mitochondrial biology.
Mitochondrial cellular organization and shape fluctuations are differentially modulated by cytoskeletal networks.
Mitochondrial pores at the crossroad between cell death and inflammatory signaling.
Highly-purified rapidly expanding clones, RECs, are superior for functional-mitochondrial transfer.
SnapShot: Mitochondrial signaling.
Spatial mapping of mitochondrial networks and bioenergetics in lung cancer.
OPA1 disease-causing mutants have domain-specific effects on mitochondrial ultrastructure and fusion.
HIF1α-BNIP3-mediated mitophagy protects against renal fibrosis by decreasing ROS and inhibiting activation of the NLRP3 inflammasome.
Inhibition of ATP synthase reverse activity restores energy homeostasis in mitochondrial pathologies.
Cyclophilin D-mediated Mitochondrial Permeability Transition Regulates Mitochondrial Function.
TRAK adaptors regulate the recruitment and activation of dynein and kinesin in mitochondrial transport.
Exploring the role of mitochondria transfer/transplant and their long-non-coding RNAs in regenerative therapies for skin aging.
A novel approach to measure complex V ATP hydrolysis in frozen cell lysates and tissue homogenates.
Mitochondrial Lon-induced mitophagy benefits hypoxic resistance via Ca2+-dependent FUNDC1 phosphorylation at the ER-mitochondria interface.
Mitochondrial protein transport: Versatility of translocases and mechanisms.
CARD-only proteins regulate in vivo inflammasome responses and ameliorate gout.
NAD+ precursor supplementation prevents mtRNA/RIG-I-dependent inflammation during kidney injury.
The multifaceted roles of mitochondria.
Metabolic sensing and control in mitochondria.

Mitochondrion. 2023 Mar 10. pii: S1567-7249(23)00028-4. [Epub ahead of print]70 20-30

Augmented Parkin-dependent mitophagy underlies the hepatoprotective effect of remote ischemic conditioning used prior to hemorrhagic shock.

Avinash Naraiah Mukkala, Raluca Petrut, Rachel Goldfarb, Erika Leigh Beroncal, Chung Ho Leung, Zahra Khan, Menachem Ailenberg, Mirjana Jerkic, Ana C Andreazza, Shawn G Rhind, Marc G Jeschke, Andras Kapus, Ori D Rotstein.

  BACKGROUND AND AIMS: Hemorrhagic shock-resuscitation (HSR) following trauma contributes to organ dysfunction by causing ischemia-reperfusion injury (IRI). We previously showed that 'remote ischemic preconditioning' (RIPC) exerted multi-organ protection from IRI. Maintenance of mitochondrial quality by clearance of dysfunctional mitochondria via mitophagy is vital in restoring organ integrity. We hypothesized that parkin-dependent mitophagy played a role in RIPC-induced hepatoprotection following HSR.METHODS: The hepatoprotective effect of RIPC in a murine model of HSR-IRI was investigated in wild type and parkin-/- animals. Mice were subjected to HSR ± RIPC and blood and organs were collected, followed by cytokine ELISAs, histology, qPCR, Western blots, and transmission electron microscopy.
RESULTS: HSR increased hepatocellular injury, as measured by plasma ALT and liver necrosis, while antecedent RIPC prevented this injury; in parkin-/- mice, RIPC failed to exert hepatoprotection. The ability of RIPC to lessen HSR-induced rises in plasma IL-6 and TNFα, was lost in parkin-/- mice. While RIPC alone did not induce mitophagy, the application of RIPC prior to HSR caused a synergistic increase in mitophagy, this increase was not observed in parkin-/- mice. RIPC induced shifts in mitochondrial morphology favoring mitophagy in WT but not in parkin-/- animals.
CONCLUSIONS: RIPC was hepatoprotective in WT mice following HSR but not in parkin-/- mice. Loss of protection in parkin-/- mice corresponded with the failure of RIPC plus HSR to upregulate the mitophagic process. Improving mitochondrial quality by modulating mitophagy, may prove to be an attractive therapeutic target in disease processes caused by IRI.

Keywords:  Hemorrhagic shock-resuscitation; Ischemia–reperfusion injury; Mitochondria; Mitochondrial quality control; Parkin-dependent mitophagy

DOI:  https://doi.org/10.1016/j.mito.2023.03.002
BMC Med. 2023 Mar 16. 21(1): 56

Exogenous mitochondrial transplantation improves survival and neurological outcomes after resuscitation from cardiac arrest.

Kei Hayashida, Ryosuke Takegawa, Yusuke Endo, Tai Yin, Rishabh C Choudhary, Tomoaki Aoki, Mitsuaki Nishikimi, Atsushi Murao, Eriko Nakamura, Muhammad Shoaib, Cyrus Kuschner, Santiago J Miyara, Junhwan Kim, Koichiro Shinozaki, Ping Wang, Lance B Becker.

  BACKGROUND: Mitochondrial transplantation (MTx) is an emerging but poorly understood technology with the potential to mitigate severe ischemia-reperfusion injuries after cardiac arrest (CA). To address critical gaps in the current knowledge, we test the hypothesis that MTx can improve outcomes after CA resuscitation.METHODS: This study consists of both in vitro and in vivo studies. We initially examined the migration of exogenous mitochondria into primary neural cell culture in vitro. Exogenous mitochondria extracted from the brain and muscle tissues of donor rats and endogenous mitochondria in the neural cells were separately labeled before co-culture. After a period of 24 h following co-culture, mitochondrial transfer was observed using microscopy. In vitro adenosine triphosphate (ATP) contents were assessed between freshly isolated and frozen-thawed mitochondria to compare their effects on survival. Our main study was an in vivo rat model of CA in which rats were subjected to 10 min of asphyxial CA followed by resuscitation. At the time of achieving successful resuscitation, rats were randomly assigned into one of three groups of intravenous injections: vehicle, frozen-thawed, or fresh viable mitochondria. During 72 h post-CA, the therapeutic efficacy of MTx was assessed by comparison of survival rates. The persistence of labeled donor mitochondria within critical organs of recipient animals 24 h post-CA was visualized via microscopy.
RESULTS: The donated mitochondria were successfully taken up into cultured neural cells. Transferred exogenous mitochondria co-localized with endogenous mitochondria inside neural cells. ATP content in fresh mitochondria was approximately four times higher than in frozen-thawed mitochondria. In the in vivo survival study, freshly isolated functional mitochondria, but not frozen-thawed mitochondria, significantly increased 72-h survival from 55 to 91% (P = 0.048 vs. vehicle). The beneficial effects on survival were associated with improvements in rapid recovery of arterial lactate and glucose levels, cerebral microcirculation, lung edema, and neurological function. Labeled mitochondria were observed inside the vital organs of the surviving rats 24 h post-CA.
CONCLUSIONS: MTx performed immediately after resuscitation improved survival and neurological recovery in post-CA rats. These results provide a foundation for future studies to promote the development of MTx as a novel therapeutic strategy to save lives currently lost after CA.

Keywords:  Cardiac arrest; Ischemia and reperfusion; Mitochondria; Mitochondrial transplantation

DOI:  https://doi.org/10.1186/s12916-023-02759-0
EMBO Rep. 2023 Mar 17. e56114

Mitochondrial-derived vesicles retain membrane potential and contain a functional ATP synthase.

Reut Hazan Ben-Menachem, Dvora Lintzer, Tamar Ziv, Koyeli Das, Irit Rosenhek-Goldian, Ziv Porat, Hila Ben Ami Pilo, Sharon Karniely, Ann Saada, Neta Regev-Rudzki, Ophry Pines.

  Vesicular transport is a means of communication. While cells can communicate with each other via secretion of extracellular vesicles, less is known regarding organelle-to organelle communication, particularly in the case of mitochondria. Mitochondria are responsible for the production of energy and for essential metabolic pathways in the cell, as well as fundamental processes such as apoptosis and aging. Here, we show that functional mitochondria isolated from Saccharomyces cerevisiae release vesicles, independent of the fission machinery. We isolate these mitochondrial-derived vesicles (MDVs) and find that they are relatively uniform in size, of about 100 nm, and carry selective protein cargo enriched for ATP synthase subunits. Remarkably, we further find that these MDVs harbor a functional ATP synthase complex. We demonstrate that these vesicles have a membrane potential, produce ATP, and seem to fuse with naive mitochondria. Our findings reveal a possible delivery mechanism of ATP-producing vesicles, which can potentially regenerate ATP-deficient mitochondria and may participate in organelle-to-organelle communication.

Keywords:  ATP synthase; membrane potential; mitochondria; mitochondrial-derived vesicles; protein distribution

DOI:  https://doi.org/10.15252/embr.202256114
Mol Cell. 2023 Mar 16. pii: S1097-2765(23)00118-1. [Epub ahead of print]83(6): 911-926

Omics-based approaches for the systematic profiling of mitochondrial biology.

Jasmin Adriana Schäfer, F X Reymond Sutandy, Christian Münch.

Mitochondria are essential for cellular functions such as metabolism and apoptosis. They dynamically adapt to the changing environmental demands by adjusting their protein, nucleic acid, metabolite, and lipid contents. In addition, the mitochondrial components are modulated on different levels in response to changes, including abundance, activity, and interaction. A wide range of omics-based approaches has been developed to be able to explore mitochondrial adaptation and how mitochondrial function is compromised in disease contexts. Here, we provide an overview of the omics methods that allow us to systematically investigate the different aspects of mitochondrial biology. In addition, we show examples of how these methods have provided new biological insights. The emerging use of these toolboxes provides a more comprehensive understanding of the processes underlying mitochondrial function.

DOI: https://doi.org/10.1016/j.molcel.2023.02.015
Sci Rep. 2023 Mar 11. 13(1): 4065

Mitochondrial cellular organization and shape fluctuations are differentially modulated by cytoskeletal networks.

Agustina Belén Fernández Casafuz, María Cecilia De Rossi, Luciana Bruno.

The interactions between mitochondria and the cytoskeleton have been found to alter mitochondrial function; however, the mechanisms underlying this phenomenon are largely unknown. Here, we explored how the integrity of the cytoskeleton affects the cellular organization, morphology and mobility of mitochondria in Xenopus laevis melanocytes. Cells were imaged in control condition and after different treatments that selectively affect specific cytoskeletal networks (microtubules, F-actin and vimentin filaments). We observed that mitochondria cellular distribution and local orientation rely mostly on microtubules, positioning these filaments as the main scaffolding of mitochondrial organization. We also found that cytoskeletal networks mold mitochondria shapes in distinct ways: while microtubules favor more elongated organelles, vimentin and actin filaments increase mitochondrial bending, suggesting the presence of mechanical interactions between these filaments and mitochondria. Finally, we identified that microtubule and F-actin networks play opposite roles in mitochondria shape fluctuations and mobility, with microtubules transmitting their jittering to the organelles and F-actin restricting the organelles motion. All our results support that cytoskeleton filaments interact mechanically with mitochondria and transmit forces to these organelles molding their movements and shapes.

DOI: https://doi.org/10.1038/s41598-023-31121-w
Mol Cell. 2023 Mar 16. pii: S1097-2765(23)00124-7. [Epub ahead of print]83(6): 843-856

Mitochondrial pores at the crossroad between cell death and inflammatory signaling.

Hector Flores-Romero, Shashank Dadsena, Ana J García-Sáez.

  Mitochondria are cellular organelles with a major role in many cellular processes, including not only energy production, metabolism, and calcium homeostasis but also regulated cell death and innate immunity. Their proteobacterial origin makes them a rich source of potent immune agonists, normally hidden within the mitochondrial membrane barriers. Alteration of mitochondrial permeability through mitochondrial pores thus provides efficient mechanisms not only to communicate mitochondrial stress to the cell but also as a key event in the integration of cellular responses. In this regard, eukaryotic cells have developed diverse signaling networks that sense and respond to the release of mitochondrial components into the cytosol and play a key role in controlling cell death and inflammatory pathways. Modulating pore formation at mitochondria through direct or indirect mechanisms may thus open new opportunities for therapy. In this review, we discuss the current understanding of the structure and molecular mechanisms of mitochondrial pores and how they function at the interface between cell death and inflammatory signaling to regulate cellular outcomes.

Keywords:  BAK; BAX; VDAC; apoptosis; gasdermin; inflammation; mPTP; membrane pore

DOI:  https://doi.org/10.1016/j.molcel.2023.02.021
Stem Cell Res Ther. 2023 Mar 16. 14(1): 40

Highly-purified rapidly expanding clones, RECs, are superior for functional-mitochondrial transfer.

Jiahao Yang, Lu Liu, Yasuaki Oda, Keisuke Wada, Mako Ago, Shinichiro Matsuda, Miho Hattori, Tsukimi Goto, Yuki Kawashima, Yumi Matsuzaki, Takeshi Taketani.

  BACKGROUND: Mitochondrial dysfunction caused by mutations in mitochondrial DNA (mtDNA) or nuclear DNA, which codes for mitochondrial components, are known to be associated with various genetic and congenital disorders. These mitochondrial disorders not only impair energy production but also affect mitochondrial functions and have no effective treatment. Mesenchymal stem cells (MSCs) are known to migrate to damaged sites and carry out mitochondrial transfer. MSCs grown using conventional culture methods exhibit heterogeneous cellular characteristics. In contrast, highly purified MSCs, namely the rapidly expanding clones (RECs) isolated by single-cell sorting, display uniform MSCs functionality. Therefore, we examined the differences between RECs and MSCs to assess the efficacy of mitochondrial transfer.METHODS: We established mitochondria-deficient cell lines (ρ0 A549 and ρ0 HeLa cell lines) using ethidium bromide. Mitochondrial transfer from RECs/MSCs to ρ0 cells was confirmed by PCR and flow cytometry analysis. We examined several mitochondrial functions including ATP, reactive oxygen species, mitochondrial membrane potential, and oxygen consumption rate (OCR). The route of mitochondrial transfer was identified using inhibition assays for microtubules/tunneling nanotubes, gap junctions, or microvesicles using transwell assay and molecular inhibitors.
RESULTS: Co-culture of ρ0 cells with MSCs or RECs led to restoration of the mtDNA content. RECs transferred more mitochondria to ρ0 cells compared to that by MSCs. The recovery of mitochondrial function, including ATP, OCR, mitochondrial membrane potential, and mitochondrial swelling in ρ0 cells co-cultured with RECs was superior than that in cells co-cultured with MSCs. Inhibition assays for each pathway revealed that RECs were sensitive to endocytosis inhibitor, dynasore.
CONCLUSIONS: RECs might serve as a potential therapeutic strategy for diseases linked to mitochondrial dysfunction by donating healthy mitochondria.

Keywords:  Mesenchymal stem cells (MSCs); Mitochondrial dysfunction; Mitochondrial transfer; Rapidly expanding clones (RECs)

DOI:  https://doi.org/10.1186/s13287-023-03274-y
Mol Cell. 2023 Mar 16. pii: S1097-2765(23)00028-X. [Epub ahead of print]83(6): 1012-1012.e1

SnapShot: Mitochondrial signaling.

Taylor A Poor, Navdeep S Chandel.

Mitochondria have emerged as signaling organelles with roles beyond their well-established function in generating ATP and metabolites for macromolecule synthesis. Healthy mitochondria integrate various physiologic inputs and communicate signals that control cell function or fate as well as adaptation to stress. Dysregulation of these mitochondrial signaling networks are linked to pathology. Here we outline a few modes of signaling between the mitochondrion and the cytoplasm. To view this SnapShot, open or download the PDF.

DOI: https://doi.org/10.1016/j.molcel.2023.01.008
Nature. 2023 Mar 15.

Spatial mapping of mitochondrial networks and bioenergetics in lung cancer.

Mingqi Han, Eric A Bushong, Mayuko Segawa, Alexandre Tiard, Alex Wong, Morgan R Brady, Milica Momcilovic, Dane M Wolf, Ralph Zhang, Anton Petcherski, Matthew Madany, Shili Xu, Jason T Lee, Masha V Poyurovsky, Kellen Olszewski, Travis Holloway, Adrian Gomez, Maie St John, Steven M Dubinett, Carla M Koehler, Orian S Shirihai, Linsey Stiles, Aaron Lisberg, Stefano Soatto, Saman Sadeghi, Mark H Ellisman, David B Shackelford.

Mitochondria are critical to the governance of metabolism and bioenergetics in cancer cells1. The mitochondria form highly organized networks, in which their outer and inner membrane structures define their bioenergetic capacity2,3. However, in vivo studies delineating the relationship between the structural organization of mitochondrial networks and their bioenergetic activity have been limited. Here we present an in vivo structural and functional analysis of mitochondrial networks and bioenergetic phenotypes in non-small cell lung cancer (NSCLC) using an integrated platform consisting of positron emission tomography imaging, respirometry and three-dimensional scanning block-face electron microscopy. The diverse bioenergetic phenotypes and metabolic dependencies we identified in NSCLC tumours align with distinct structural organization of mitochondrial networks present. Further, we discovered that mitochondrial networks are organized into distinct compartments within tumour cells. In tumours with high rates of oxidative phosphorylation (OXPHOSHI) and fatty acid oxidation, we identified peri-droplet mitochondrial networks wherein mitochondria contact and surround lipid droplets. By contrast, we discovered that in tumours with low rates of OXPHOS (OXPHOSLO), high glucose flux regulated perinuclear localization of mitochondria, structural remodelling of cristae and mitochondrial respiratory capacity. Our findings suggest that in NSCLC, mitochondrial networks are compartmentalized into distinct subpopulations that govern the bioenergetic capacity of tumours.

DOI: https://doi.org/10.1038/s41586-023-05793-3
Proc Natl Acad Sci U S A. 2023 Mar 21. 120(12): e2207471120

OPA1 disease-causing mutants have domain-specific effects on mitochondrial ultrastructure and fusion.

Benjamín Cartes-Saavedra, Daniel Lagos, Josefa Macuada, Duxan Arancibia, Florence Burté, Marcela K Sjöberg-Herrera, María Estela Andrés, Rita Horvath, Patrick Yu-Wai-Man, György Hajnóczky, Verónica Eisner.

  Inner mitochondrial membrane fusion and cristae shape depend on optic atrophy protein 1, OPA1. Mutations in OPA1 lead to autosomal dominant optic atrophy (ADOA), an important cause of inherited blindness. The Guanosin Triphosphatase (GTPase) and GTPase effector domains (GEDs) of OPA1 are essential for mitochondrial fusion; yet, their specific roles remain elusive. Intriguingly, patients carrying OPA1 GTPase mutations have a higher risk of developing more severe multisystemic symptoms in addition to optic atrophy, suggesting pathogenic contributions for the GTPase and GED domains, respectively. We studied OPA1 GTPase and GED mutations to understand their domain-specific contribution to protein function by analyzing patient-derived cells and gain-of-function paradigms. Mitochondria from OPA1 GTPase (c.870+5G>A and c.889C>T) and GED (c.2713C>T and c.2818+5G>A) mutants display distinct aberrant cristae ultrastructure. While all OPA1 mutants inhibited mitochondrial fusion, some GTPase mutants resulted in elongated mitochondria, suggesting fission inhibition. We show that the GED is dispensable for fusion and OPA1 oligomer formation but necessary for GTPase activity. Finally, splicing defect mutants displayed a posttranslational haploinsufficiency-like phenotype but retained domain-specific dysfunctions. Thus, OPA1 domain-specific mutants result in distinct impairments in mitochondrial dynamics, providing insight into OPA1 function and its contribution to ADOA pathogenesis and severity.

Keywords:  ADOA; OPA1; cristae; dynamics; mitochondria

DOI:  https://doi.org/10.1073/pnas.2207471120
Cell Death Dis. 2023 Mar 17. 14(3): 200

HIF1α-BNIP3-mediated mitophagy protects against renal fibrosis by decreasing ROS and inhibiting activation of the NLRP3 inflammasome.

Jialin Li, Qisheng Lin, Xinghua Shao, Shu Li, Xuying Zhu, Jingkui Wu, Shan Mou, Leyi Gu, Qin Wang, Minfang Zhang, Kaiqi Zhang, Jiayue Lu, Zhaohui Ni.

Chronic kidney disease affects approximately 14.3% of people worldwide. Tubulointerstitial fibrosis is the final stage of almost all progressive CKD. To date, the pathogenesis of renal fibrosis remains unclear, and there is a lack of effective treatments, leading to renal replacement therapy. Mitophagy is a type of selective autophagy that has been recognized as an important way to remove dysfunctional mitochondria and abrogate the excessive accumulation of mitochondrial-derived reactive oxygen species (ROS) to balance the function of cells. However, the role of mitophagy and its regulation in renal fibrosis need further examination. In this study, we showed that mitophagy was induced in renal tubular epithelial cells in renal fibrosis. After silencing BNIP3, mitophagy was abolished in vivo and in vitro, indicating the important effect of the BNIP3-dependent pathway on mitophagy. Furthermore, in unilateral ureteral obstruction (UUO) models and hypoxic conditions, the production of mitochondrial ROS, mitochondrial damage, activation of the NLRP3 inflammasome, and the levels of αSMA and TGFβ1 increased significantly following BNIP3 gene deletion or silencing. Following silencing BNIP3 and pretreatment with mitoTEMPO or MCC950, the protein levels of αSMA and TGFβ1 decreased significantly in HK-2 cells under hypoxic conditions. These findings demonstrated that HIF1α-BNIP3-mediated mitophagy played a protective role against hypoxia-induced renal epithelial cell injury and renal fibrosis by reducing mitochondrial ROS and inhibiting activation of the NLRP3 inflammasome.

DOI: https://doi.org/10.1038/s41419-023-05587-5
EMBO J. 2023 Mar 13. e111699

Inhibition of ATP synthase reverse activity restores energy homeostasis in mitochondrial pathologies.

Rebeca Acin-Perez, Cristiane Benincá, Lucia Fernandez Del Rio, Cynthia Shu, Siyouneh Baghdasarian, Vanessa Zanette, Christoph Gerle, Chimari Jiko, Ramzi Khairallah, Shaharyar Khan, David Rincon Fernandez Pacheco, Byourak Shabane, Karel Erion, Ruchi Masand, Sundeep Dugar, Cristina Ghenoiu, George Schreiner, Linsey Stiles, Marc Liesa, Orian S Shirihai.

  The maintenance of cellular function relies on the close regulation of adenosine triphosphate (ATP) synthesis and hydrolysis. ATP hydrolysis by mitochondrial ATP Synthase (CV) is induced by loss of proton motive force and inhibited by the mitochondrial protein ATPase inhibitor (ATPIF1). The extent of CV hydrolytic activity and its impact on cellular energetics remains unknown due to the lack of selective hydrolysis inhibitors of CV. We find that CV hydrolytic activity takes place in coupled intact mitochondria and is increased by respiratory chain defects. We identified (+)-Epicatechin as a selective inhibitor of ATP hydrolysis that binds CV while preventing the binding of ATPIF1. In cells with Complex-III deficiency, we show that inhibition of CV hydrolytic activity by (+)-Epichatechin is sufficient to restore ATP content without restoring respiratory function. Inhibition of CV-ATP hydrolysis in a mouse model of Duchenne Muscular Dystrophy is sufficient to improve muscle force without any increase in mitochondrial content. We conclude that the impact of compromised mitochondrial respiration can be lessened using hydrolysis-selective inhibitors of CV.

Keywords:  ATP hydrolysis; ATPase Inhibitor (ATPIF1); Complex V; epicatechin; muscular dystrophy

DOI:  https://doi.org/10.15252/embj.2022111699
Curr Pharm Des. 2023 Mar 13.

Cyclophilin D-mediated Mitochondrial Permeability Transition Regulates Mitochondrial Function.

Shaoyun Zhou, Qinwei Yu, Luyong Zhang, Zhenzhou Jiang.

  BACKGROUND: Mitochondria are multifunctional organelles, which participate in biochemical processes. Mitochondria acts as primary energy producers and biosynthetic centers of cells, which are involved in oxidative stress responses and cell signaling transduction. Among numerous potential mechanisms of mitochondrial dysfunction, the opening of the mitochondrial permeability transition pore (mPTP) is a major determinant of mitochondrial dysfunction to induce cellular damage or death. A plenty of studies have provided evidence that the abnormal opening of mPTP induces the loss of mitochondrial membrane potential, the impairment calcium homeostasis and the decrease of ATP production. Cyclophilin D (CypD), localized in the mitochondrial transition pore, is a mitochondrial chaperone that has been regarded as a prominent mediator of mPTP.METHODS: This review describes the relationship between CypD, mPTP, and CypD-mPTP inhibitors through systematic investigation of recent relevant literature.
RESULTS: Here, we have highlighted that inhibiting the activity of CypD protects models of some diseases, including ischaemia/reperfusion injury (IRI), neurodegenerative disorders and so on. Knockdown studies have demonstrated that CypD possibly is mediated by its peptidyl-prolyl cis-trans isomerase activity, while the primary targets of CypD remain obscure. The target of CypD-mPTP inhibitor can alleviate mPTP opening-induced cell death. The present review is focused on the role of CypD as a prominent mediator of the mPTP, further providing insight into the physiological function of mPTP and its regulation by CypD.
CONCLUSION: Blocking the opening of mPTP by inhibiting CypD might be a new promising approach for suppressing cell death, which will suggest novel therapeutic approaches for mitochondria-related diseases.

Keywords:  cyclophilin D; mechanisms; mitochondria; mitochondrial permeability transition pore

DOI:  https://doi.org/10.2174/1381612829666230313111314
Nat Commun. 2023 Mar 13. 14(1): 1376

TRAK adaptors regulate the recruitment and activation of dynein and kinesin in mitochondrial transport.

John T Canty, Andrew Hensley, Merve Aslan, Amanda Jack, Ahmet Yildiz.

Mitochondrial transport along microtubules is mediated by Miro1 and TRAK adaptors that recruit kinesin-1 and dynein-dynactin. To understand how these opposing motors are regulated during mitochondrial transport, we reconstitute the bidirectional transport of Miro1/TRAK along microtubules in vitro. We show that the coiled-coil domain of TRAK activates dynein-dynactin and enhances the motility of kinesin-1 activated by its cofactor MAP7. We find that TRAK adaptors that recruit both motors move towards kinesin-1's direction, whereas kinesin-1 is excluded from binding TRAK transported by dynein-dynactin, avoiding motor tug-of-war. We also test the predictions of the models that explain how mitochondrial transport stalls in regions with elevated Ca2+. Transport of Miro1/TRAK by kinesin-1 is not affected by Ca2+. Instead, we demonstrate that the microtubule docking protein syntaphilin induces resistive forces that stall kinesin-1 and dynein-driven motility. Our results suggest that mitochondrial transport stalls by Ca2+-mediated recruitment of syntaphilin to the mitochondrial membrane, not by disruption of the transport machinery.

DOI: https://doi.org/10.1038/s41467-023-36945-8
Mitochondrion. 2023 Mar 13. pii: S1567-7249(23)00029-6. [Epub ahead of print]

Exploring the role of mitochondria transfer/transplant and their long-non-coding RNAs in regenerative therapies for skin aging.

Sebastian Peñaherrera, Cristina Ruiz, Verónica Castañeda, Kathryn Livingston, Diego Barba, Verónica A Burzio, Andrés Caicedo, Keshav K Singh.

  Advancing age and environmental stressors lead to mitochondrial dysfunction in the skin, inducing premature aging, impaired regeneration, and greater risk of cancer. Cells rely on the communication between the mitochondria and the nucleus by tight regulation of long non-coding RNAs (lncRNAs) to avoid premature aging and maintain healthy skin. LncRNAs act as key regulators of cell proliferation, differentiation, survival, and maintenance of skin structure. However, research on how the lncRNAs are dysregulated during aging and due to stressors is needed to develop therapies to regenerate skin's function and structure. In this article, we discuss how age and environmental stressors may alter lncRNA homeodynamics, compromising cell survival and skin health, and how these factors may become inducers of skin aging. We describe skin cell types and how they depend on mitochondrial function and lncRNAs. We also provide a list of mitochondria localized and nuclear lncRNAs that can serve to better understand skin aging. Using bioinformatic prediction tools, we predict possible functions of lncRNAs based on their subcellular localization. We also search for experimentally determined protein interactions and the biological processes involved. Finally, we provide therapeutic strategies based on gene editing and mitochondria transfer/transplant (AMT/T) to restore lncRNA regulation and skin health. This article offers a unique perspective in understanding and defining the therapeutic potential of mitochondria localized lncRNAs (mt-lncRNAs) produced and AMT/T to treat skin aging and related diseases.

Keywords:  AMT/T; Skin; aging; artificial mitochondrial transfer / transplant; gene editing; lncRNAs; mitochondria

DOI:  https://doi.org/10.1016/j.mito.2023.02.012
Life Sci Alliance. 2023 Apr;pii: e202201628. [Epub ahead of print]6(4):

A novel approach to measure complex V ATP hydrolysis in frozen cell lysates and tissue homogenates.

Lucia Fernandez-Del-Rio, Cristiane Benincá, Frankie Villalobos, Cynthia Shu, Linsey Stiles, Marc Liesa, Ajit S Divakaruni, Rebeca Acin-Perez, Orian S Shirihai.

Mitochondrial depolarization can initiate reversal activity of ATP synthase, depleting ATP by its hydrolysis. We have recently shown that increased ATP hydrolysis contributes to ATP depletion leading to a maladaptation in mitochondrial disorders, where maximal hydrolytic capacity per CV content is increasing. However, despite its importance, ATP hydrolysis is not a commonly studied parameter because of the limitations of the currently available methods. Methods that measure CV hydrolytic activity indirectly require the isolation of mitochondria and involve the introduction of detergents, preventing their utilization in clinical studies or any high-throughput analyses. Here, we describe a novel approach to assess maximal ATP hydrolytic capacity and maximal respiratory capacity in a single assay in cell lysates, PBMCs, and tissue homogenates that were previously frozen. The methodology described here has the potential to be used in clinical samples to determine adaptive and maladaptive adjustments of CV function in diseases, with the added benefit of being able to use frozen samples in a high-throughput manner and to explore ATP hydrolysis as a drug target for disease treatment.

DOI: https://doi.org/10.26508/lsa.202201628
Cell Death Dis. 2023 Mar 16. 14(3): 199

Mitochondrial Lon-induced mitophagy benefits hypoxic resistance via Ca2+-dependent FUNDC1 phosphorylation at the ER-mitochondria interface.

Ananth Ponneri Babuharisankar, Cheng-Liang Kuo, Han-Yu Chou, Vidhya Tangeda, Chi-Chen Fan, Chung-Hsing Chen, Yung-Hsi Kao, Alan Yueh-Luen Lee.

During hypoxia, FUNDC1 acts as a mitophagy receptor and accumulates at the ER (endoplasmic reticulum)-mitochondria contact sites (EMC), also called mitochondria-associated membranes (MAM). In mitophagy, the ULK1 complex phosphorylates FUNDC1(S17) at the EMC site. However, how mitochondria sense the stress and send the signal from the inside to the outside of mitochondria to trigger mitophagy is still unclear. Mitochondrial Lon was reported to be localized at the EMC under stress although the function remained unknown. In this study, we explored the mechanism of how mitochondrial sensors of hypoxia trigger and stabilize the FUNDC1-ULK1 complex by Lon in the EMC for cell survival and cancer progression. We demonstrated that Lon is accumulated in the EMC and associated with FUNDC1-ULK1 complex to induce mitophagy via chaperone activity under hypoxia. Intriguingly, we found that Lon-induced mitophagy is through binding with mitochondrial Na+/Ca2+ exchanger (NCLX) to promote FUNDC1-ULK1-mediated mitophagy at the EMC site in vitro and in vivo. Accordingly, our findings highlight a novel mechanism responsible for mitophagy initiation under hypoxia by chaperone Lon in mitochondria through the interaction with FUNDC1-ULK1 complex at the EMC site. These findings provide a direct correlation between Lon and mitophagy on cell survival and cancer progression.

DOI: https://doi.org/10.1038/s41419-023-05723-1
Mol Cell. 2023 Mar 16. pii: S1097-2765(23)00123-5. [Epub ahead of print]83(6): 890-910

Mitochondrial protein transport: Versatility of translocases and mechanisms.

Jakob D Busch, Laura F Fielden, Nikolaus Pfanner, Nils Wiedemann.

Biogenesis of mitochondria requires the import of approximately 1,000 different precursor proteins into and across the mitochondrial membranes. Mitochondria exhibit a wide variety of mechanisms and machineries for the translocation and sorting of precursor proteins. Five major import pathways that transport proteins to their functional intramitochondrial destination have been elucidated; these pathways range from the classical amino-terminal presequence-directed pathway to pathways using internal or even carboxy-terminal targeting signals in the precursors. Recent studies have provided important insights into the structural organization of membrane-embedded preprotein translocases of mitochondria. A comparison of the different translocases reveals the existence of at least three fundamentally different mechanisms: two-pore-translocase, β-barrel switching, and transport cavities open to the lipid bilayer. In addition, translocases are physically engaged in dynamic interactions with respiratory chain complexes, metabolite transporters, quality control factors, and machineries controlling membrane morphology. Thus, mitochondrial preprotein translocases are integrated into multi-functional networks of mitochondrial and cellular machineries.

DOI: https://doi.org/10.1016/j.molcel.2023.02.020
Cell Rep. 2023 Mar 15. pii: S2211-1247(23)00276-0. [Epub ahead of print]42(3): 112265

CARD-only proteins regulate in vivo inflammasome responses and ameliorate gout.

Savita Devi, Mohanalaxmi Indramohan, Elisabeth Jäger, Jessica Carriere, Lan H Chu, Lucia de Almeida, David R Greaves, Christian Stehlik, Andrea Dorfleutner.

  Inflammatory responses are crucial for controlling infections and initiating tissue repair. However, excessive and uncontrolled inflammation causes inflammatory disease. Processing and release of the pro-inflammatory cytokines interleukin-1β (IL-1β) and IL-18 depend on caspase-1 activation within inflammasomes. Assembly of inflammasomes is initiated upon activation of cytosolic pattern recognition receptors (PRRs), followed by sequential polymerization of pyrin domain (PYD)-containing and caspase recruitment domain (CARD)-containing proteins mediated by homotypic PYD and CARD interactions. Small PYD- or CARD-only proteins (POPs and COPs, respectively) evolved in higher primates to target these crucial interactions to limit inflammation. Here, we show the ability of COPs to regulate inflammasome activation by modulating homotypic CARD-CARD interactions in vitro and in vivo. CARD16, CARD17, and CARD18 displace crucial CARD interactions between caspase-1 proteins through competitive binding and ameliorate uric acid crystal-mediated NLRP3 inflammasome activation and inflammatory disease. COPs therefore represent an important family of inflammasome regulators and ameliorate inflammatory disease.

Keywords:  ASC; CARD; COP; CP: Immunology; CP: Molecular biology; IL-1; NLRP3; caspase recruitment domain; caspase-1; gout; inflammasome; interleukin-1

DOI:  https://doi.org/10.1016/j.celrep.2023.112265
Nat Metab. 2023 Mar 13.

NAD+ precursor supplementation prevents mtRNA/RIG-I-dependent inflammation during kidney injury.

Tomohito Doke, Sarmistha Mukherjee, Dhanunjay Mukhi, Poonam Dhillon, Amin Abedini, James G Davis, Karthikeyani Chellappa, Beishan Chen, Joseph A Baur, Katalin Susztak.

Our understanding of how global changes in cellular metabolism contribute to human kidney disease remains incompletely understood. Here we show that nicotinamide adenine dinucleotide (NAD+) deficiency drives mitochondrial dysfunction causing inflammation and kidney disease development. Using unbiased global metabolomics in healthy and diseased human kidneys, we identify NAD+ deficiency as a disease signature. Furthermore using models of cisplatin- or ischaemia-reperfusion induced kidney injury in male mice we observed NAD+ depletion Supplemental nicotinamide riboside or nicotinamide mononucleotide restores NAD+ levels and improved kidney function. We find that cisplatin exposure causes cytosolic leakage of mitochondrial RNA (mtRNA) and activation of the cytosolic pattern recognition receptor retinoic acid-inducible gene I (RIG-I), both of which can be ameliorated by restoring NAD+. Male mice with RIG-I knock-out (KO) are protected from cisplatin-induced kidney disease. In summary, we demonstrate that the cytosolic release of mtRNA and RIG-I activation is an NAD+-sensitive mechanism contributing to kidney disease.

DOI: https://doi.org/10.1038/s42255-023-00761-7
Mol Cell. 2023 Mar 16. pii: S1097-2765(23)00157-0. [Epub ahead of print]83(6): 819-823

The multifaceted roles of mitochondria.

Thomas J Pucadyil, Jerry Edward Chipuk, Ying Liu, Luke O'Neill, Quan Chen.

Much more than the "powerhouse" of the cell, mitochondria have emerged as critical hubs involved in metabolism, cell death, inflammation, signaling, and stress responses. To open our mitochondria focus issue, we asked several scientists to share the unanswered questions, emerging themes, and topics of investigation that excite them.

DOI: https://doi.org/10.1016/j.molcel.2023.02.030
Mol Cell. 2023 Mar 16. pii: S1097-2765(23)00119-3. [Epub ahead of print]83(6): 877-889

Metabolic sensing and control in mitochondria.

Yuyang Liu, Kıvanç Birsoy.

Mitochondria are membrane-enclosed organelles with endosymbiotic origins, harboring independent genomes and a unique biochemical reaction network. To perform their critical functions, mitochondria must maintain a distinct biochemical environment and coordinate with the cytosolic metabolic networks of the host cell. This coordination requires them to sense and control metabolites and respond to metabolic stresses. Indeed, mitochondria adopt feedback or feedforward control strategies to restrain metabolic toxicity, enable metabolic conservation, ensure stable levels of key metabolites, allow metabolic plasticity, and prevent futile cycles. A diverse panel of metabolic sensors mediates these regulatory circuits whose malfunctioning leads to inborn errors of metabolism with mild to severe clinical manifestations. In this review, we discuss the logic and molecular basis of metabolic sensing and control in mitochondria. The past research outlined recurring patterns in mitochondrial metabolic sensing and control and highlighted key knowledge gaps in this organelle that are potentially addressable with emerging technological breakthroughs.

DOI: https://doi.org/10.1016/j.molcel.2023.02.016