bims-mecmid Biomed News
on Membrane communication in mitochondrial dynamics
Issue of 2022–03–06
sixteen papers selected by
Mauricio Cardenas Rodriguez, University of Padova
  1. Hydrogen sulfide diminishes activation of adventitial fibroblasts via the inhibition of mitochondrial fission.
  2. L22 ribosomal protein is involved in dynamin-related protein 1-mediated gastric carcinoma progression.
  3. Long-lived mitochondrial proteins and why they exist.
  4. Nrf2 Deficiency Attenuates Testosterone Efficiency in Ameliorating Mitochondrial Function of the Substantia Nigra in Aged Male Mice.
  5. Correction to: Mitochondrial dynamics regulators: implications for therapeutic intervention in cancer.
  6. Conditional deletion of myeloid-specific mitofusin 2 but not mitofusin 1 promotes kidney fibrosis.
  7. Bypassing the nuclear gate: A non-canonical entry pathway for the mitochondrial pyruvate dehydrogenase complex.
  8. Tom70-based transcriptional regulation of mitochondrial biogenesis and aging.
  9. SERAC1 is a component of the mitochondrial serine transporter complex required for the maintenance of mitochondrial DNA.
  10. Peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) overexpression alleviates endoplasmic reticulum stress after acute kidney injury.
  11. Atorvastatin Restores PPARα Inhibition of Lipid Metabolism Disorders by Downregulating miR-21 Expression to Improve Mitochondrial Function and Alleviate Diabetic Nephropathy Progression.
  12. MFN2-driven mitochondria-to-nucleus tethering allows a non-canonical nuclear entry pathway of the mitochondrial pyruvate dehydrogenase complex.
  13. Ratiometric Imaging of Mitochondrial Hydrogen Peroxide in Aβ42-Mediated Neurotoxicity.
  14. The ER membrane complex (EMC) can functionally replace the Oxa1 insertase in mitochondria.
  15. Renoprotective potential of myo-inositol on diabetic kidney disease: Focus on the role of the PINK1/Parkin pathway and mitophagy receptors.
  16. Mitochondrial ROS Produced by Skeletal Muscle Mitochondria Promote the Decisive Signal for UPRmt Activation.
  1. J Cardiovasc Pharmacol. 2022 Feb 24.
    Hydrogen sulfide diminishes activation of adventitial fibroblasts via the inhibition of mitochondrial fission.
    Zhao-Yang Lu, Chun-Ling Guo, Bin Yang, Yao Yao, Zhuo-Jing Yang, Yu-Xin Gong, Jing-Yao Yang, Wen-Yuan Dong, Jun Yang, Hai-Bing Yang, Hui-Min Liu, Bao Li.
       ABSTRACT: Activation of adventitial fibroblasts (AFs) upon vascular injury contributes to vascular remodeling. Hydrogen sulfide (H2S), a gaseous signal molecule, modulates various cardiovascular functions. The aim of this study was to explore whether exogenous H2S ameliorates transforming growth factor-β1 (TGF-β1) induced activation of adventitial fibroblasts (AFs), and if so, to determine the underlying molecular mechanisms. Immunofluorescent staining, and western blot were employed to determine the expression of collagen I and α-smooth muscle-actin (α-SMA). The proliferation and migration of AFs were performed by using cell counting kit-8 (CCK-8) and Transwell assay, respectively. The mitochondrial morphology was assessed by MitoTracker Red staining. The activation of signaling pathway was evaluated by western blot. The mitochondrial reactive oxygen species (mtROS) and mitochondrial membrane potential were determined by MitoSOX and JC-1 (5,5',6,6'-tetrachloro-1,1,3,3'-tetraethylbenzimidazolyl carbocyanine iodide) staining. Our study demonstrated exogenous H2S treatment dramatically suppressed TGF-β1 induced AF proliferation, migration, and phenotypic transition by blockage of dynamin-related protein 1 (Drp1) mediated mitochondrial fission and regulated mtROS generation. Moreover, exogenous H2S reversed TGF-β1 induced mitochondrial fission and AF activation by modulating Rho-associated protein kinase 1 (ROCK1) dependent phosphorylation of Drp1. In conclusion, our results suggested that exogenous H2S attenuates TGF-β1 induced AF activation via suppression of Drp1-mediated mitochondrial fission in a ROCK1-dependent fashion.
    DOI:  https://doi.org/10.1097/FJC.0000000000001250
  2. Bioengineered. 2022 03;13(3): 6650-6664
    L22 ribosomal protein is involved in dynamin-related protein 1-mediated gastric carcinoma progression.
    Jianghong Cheng, Zizhuo Sha, Ruisan Zhang, Jinghao Ge, Peng Chen, Xuefeng Kuang, Jiazhi Chang, Kai Ren, Xianyang Luo, Shuai Chen, Xingchun Gou.
      Mitochondrial fission depends on dynamin-related protein 1 (Drp1) guanosine triphosphatase activity. Although there is some association between Drp1 and gastric cancer, the detailed mechanism remains largely unknown. In this study, the elevation of Drp1 was observed in human gastric carcinoma specimens including gastric mixed adenocarcinoma tissues, gastric intestinal-type adenocarcinoma tissues, and human gastric cancer cells compared to normal control, but not in diffuse gastric adenocarcinoma tissues. Gastric cancer patients with high Drp1 harbored advanced pathological stages and poor progression-free survival probability compared to those with low Drp1. Mdivi-1-mediated inactivation of Drp1 robustly inhibited cell viability and tumor growth but conversely induced cell apoptotic events in vitro and in vivo. Based on the Encyclopedia of RNA Interactomes Starbase, L22 ribosomal protein (RPL22) was recognized as the potential downstream oncogene of Drp1. Clinically, the significant correlation of Drp1 and RPL22 was also verified. Mechanistically, Drp1 inactivation did not affect the accumulation of RPL22 in gastric carcinoma. However, the intracellular distribution of RPL22 had an endonuclear location in Drp1-inactivated tumors. Of note, Drp1 inactivation notably reduced the expression of cytoplasmic RPL22 and increased its nuclear level in gastric cancer cells. Collectively, Drp1 had high levels in human gastric carcinoma specimens and could serve as a potential diagnostic and prognostic biomarker in gastric carcinoma. The Drp1 inactivation-mediated anti-proliferative and pro-apoptosis effects on gastric cancer were possibly associated with nuclear import of RPL22. This knowledge may provide new therapeutic tools for treating gastric carcinoma via targeting mitochondria-related ribosome pathway.
    DOI:  https://doi.org/10.1080/21655979.2022.2045842
  3. Trends Cell Biol. 2022 Feb 24. pii: S0962-8924(22)00034-4. [Epub ahead of print]
    Long-lived mitochondrial proteins and why they exist.
    Ewa Bomba-Warczak, Jeffrey N Savas.
      Intracellular long-lived proteins (LLPs) provide structural support for several highly stable protein complexes and assemblies that play essential roles in ensuring cellular homeostasis and function. Recently, mitochondrial long-lived proteins (mt-LLPs) were discovered within inner mitochondria membranes (IMMs) and cristae invagination in tissues with old postmitotic cells. This observation is at odds with the fact that mitochondria are highly dynamic organelles that are continually remodeled through processes of fission, fusion, biogenesis, and multiple quality control pathways. In this opinion article, we propose that a subset of the mitochondrial proteome persists over long time frames and these mt-LLPs provide key structural support for the lifelong maintenance of mitochondrial structure.
    Keywords:  cristae ultrastructure; long-lived proteins; mitochondria; mitochondrial dynamics; protein turnover; stable structures
    DOI:  https://doi.org/10.1016/j.tcb.2022.02.001
  4. Oxid Med Cell Longev. 2022 ;2022 3644318
    Nrf2 Deficiency Attenuates Testosterone Efficiency in Ameliorating Mitochondrial Function of the Substantia Nigra in Aged Male Mice.
    Baoliang Ren, Tianyun Zhang, Qiqing Guo, Jing Che, Yunxiao Kang, Rui Cui, Yu Wang, Xiaoming Ji, Guoliang Zhang, Geming Shi.
      Reduced testosterone level is a common feature of aging in men. Aging, as a risk factor for several neurodegenerative disorders, shows declined mitochondrial function and downregulated mitochondrial biogenesis and mitochondrial dynamics. Mitochondrial biogenesis and mitochondrial dynamics are crucial in maintaining proper mitochondrial function. Supplementation with testosterone is conducive to improving mitochondrial function of males during aging. Nuclear factor erythroid 2-related factor 2 (Nrf2), a regulator of redox homeostasis, is involved in the ameliorative effects of testosterone supplementation upon aging. To explore Nrf2 role in the effects of testosterone supplementation on mitochondrial function during aging, we studied the efficiency of testosterone supplementation in improving mitochondrial function of Nrf2 knockout- (KO-) aged male mice by analyzing the changes of mitochondrial biogenesis and mitochondrial dynamics. It was found that wild-type- (WT-) aged male mice showed low mitochondrial function and expression levels of PGC-1α, NRF-1\NRF-2, and TFAM regulating mitochondrial biogenesis, as well as Drp1, Mfn1, and OPA1 controlling mitochondrial dynamics in the substantia nigra (SN). Nrf2 KO aggravated the defects above in SN of aged male mice. Testosterone supplementation to WT-aged male mice significantly ameliorated mitochondrial function and upregulated mitochondrial biogenesis and mitochondrial dynamics, which were not shown in Nrf2 KO-aged male mice due to Nrf2 deficiency. Testosterone deficiency by gonadectomy (GDX) decreased mitochondrial function, downregulated mitochondrial biogenesis, and altered mitochondrial dynamics balance in young male mice. Supplementation with testosterone to Nrf2 KO-GDX mice only ameliorated the alterations above but did not reverse them to sham level. Nrf2 deficiency attenuated testosterone efficiency in ameliorating mitochondrial function in the SN of aged male mice through mitochondrial biogenesis and mitochondrial dynamics to some extent. Activation of Nrf2 might contribute to testosterone-upregulating mitochondrial biogenesis and mitochondrial dynamics in the SN during aging to produce efficient mitochondria for ATP production.
    DOI:  https://doi.org/10.1155/2022/3644318
  5. Cell Biol Toxicol. 2022 Mar 04.
    Correction to: Mitochondrial dynamics regulators: implications for therapeutic intervention in cancer.
    Sanjay Kumar, Rahail Ashraf, Aparna C K.
      
    DOI:  https://doi.org/10.1007/s10565-021-09688-9
  6. Kidney Int. 2022 Feb 25. pii: S0085-2538(22)00160-0. [Epub ahead of print]
    Conditional deletion of myeloid-specific mitofusin 2 but not mitofusin 1 promotes kidney fibrosis.
    Divya Bhatia, Allyson Capili, Kiichi Nakahira, Thangamani Muthukumar, Lisa K Torres, Augustine M K Choi, Mary E Choi.
      Macrophages exert critical functions during kidney injury, inflammation, and tissue repair or fibrosis. Mitochondrial structural and functional aberrations due to an imbalance in mitochondrial fusion/fission processes are implicated in the pathogenesis of chronic kidney disease. Therefore, we investigated macrophage-specific functions of mitochondrial fusion proteins, mitofusin (MFN)1 and MFN2, in modulating macrophage mitochondrial dynamics, biogenesis, oxidative stress, polarization, and fibrotic response. MFN1 and MFN2 were found to be suppressed in mice after adenine diet-induced chronic kidney disease, in transforming growth factor-beta 1-treated bone marrow-derived macrophages, and in THP-1-derived human macrophages (a human leukemic cell line). However, abrogating Mfn2 but not Mfn1 in myeloid-lineage cells resulted in greater macrophage recruitment into the kidney during fibrosis and the macrophage-derived fibrotic response associated with collagen deposition culminating in worsening kidney function. Myeloid-specific Mfn1 /Mfn2 double knockout mice also showed increased adenine-induced fibrosis. Mfn2-deficient bone marrow-derived macrophages displayed enhanced polarization towards the profibrotic/M2 phenotype and impaired mitochondrial biogenesis. Macrophages in the kidney of Mfn2-deficient and double knockout but not Mfn1-deficient mice exhibited greater mitochondrial mass, size, oxidative stress and lower mitophagy under fibrotic conditions than the macrophages in the kidney of wild-type mice. Thus, downregulation of MFN2 but not MFN1 lead to macrophage polarization towards a profibrotic phenotype to promote kidney fibrosis through a mechanism involving suppression of macrophage mitophagy and dysfunctional mitochondrial dynamics.
    Keywords:  kidney fibrosis; macrophage; mitochondrial fusion; mitophagy; reactive oxygen species
    DOI:  https://doi.org/10.1016/j.kint.2022.01.030
  7. Mol Cell. 2022 Mar 03. pii: S1097-2765(22)00119-8. [Epub ahead of print]82(5): 886-888
    Bypassing the nuclear gate: A non-canonical entry pathway for the mitochondrial pyruvate dehydrogenase complex.
    Emily Boyle, Florian Wilfling.
      Zervopoulos et al. (2022) propose a non-canonical nuclear import pathway for the functional mitochondrial pyruvate dehydrogenase complex (PDC), facilitated by dynamic MFN2-mediated tethering of mitochondria to the nuclear envelope upon exposure to proliferative stimuli.
    DOI:  https://doi.org/10.1016/j.molcel.2022.02.014
  8. Elife. 2022 Mar 02. pii: e75658. [Epub ahead of print]11
    Tom70-based transcriptional regulation of mitochondrial biogenesis and aging.
    Qingqing Liu, Catherine E Chang, Alexandra C Wooldredge, Benjamin Fong, Brian K Kennedy, Chuankai Zhou.
      Mitochondrial biogenesis has two major steps: the transcriptional activation of nuclear genome-encoded mitochondrial proteins and the import of nascent mitochondrial proteins that are synthesized in the cytosol. These nascent mitochondrial proteins are aggregation-prone and can cause cytosolic proteostasis stress. The transcription factor-dependent transcriptional regulations and the TOM-TIM complex-dependent import of nascent mitochondrial proteins have been extensively studied. Yet, little is known regarding how these two steps of mitochondrial biogenesis coordinate with each other to avoid the cytosolic accumulation of these aggregation-prone nascent mitochondrial proteins. Here we show that in budding yeast, Tom70, a conserved receptor of the TOM complex, moonlights to regulate the transcriptional activity of mitochondrial proteins. Tom70's transcription regulatory role is conserved in Drosophila. The dual roles of Tom70 in both transcription/biogenesis and import of mitochondrial proteins allow the cells to accomplish mitochondrial biogenesis without compromising cytosolic proteostasis. The age-related reduction of Tom70, caused by reduced biogenesis and increased degradation of Tom70, is associated with the loss of mitochondrial membrane potential, mtDNA, and mitochondrial proteins. While loss of Tom70 accelerates aging and age-related mitochondrial defects, overexpressing TOM70 delays these mitochondrial dysfunctions and extends the replicative lifespan. Our results reveal unexpected roles of Tom70 in mitochondrial biogenesis and aging.
    Keywords:  S. cerevisiae; cell biology
    DOI:  https://doi.org/10.7554/eLife.75658
  9. Sci Transl Med. 2022 Mar 02. 14(634): eabl6992
    SERAC1 is a component of the mitochondrial serine transporter complex required for the maintenance of mitochondrial DNA.
    Hezhi Fang, Anran Xie, Miaomiao Du, Xueyun Li, Kaiqiang Yang, Yinxu Fu, Xiangshu Yuan, Runxiao Fan, Weidong Yu, Zhuohua Zhou, Tiantian Sang, Ke Nie, Jin Li, Qiongya Zhao, Zhehui Chen, Yanling Yang, Chaoyang Hong, Jianxin Lyu.
      SERAC1 deficiency is associated with the mitochondrial 3-methylglutaconic aciduria with deafness, (hepatopathy), encephalopathy, and Leigh-like disease [MEGD(H)EL] syndrome, but the role of SERAC1 in mitochondrial physiology remains unknown. Here, we generated Serac1-/- mice that mimic the major diagnostic clinical and biochemical phenotypes of the MEGD(H)EL syndrome. We found that SERAC1 localizes to the outer mitochondrial membrane and is a protein component of the one-carbon cycle. By interacting with the mitochondrial serine transporter protein SFXN1, SERAC1 facilitated and was required for SFXN1-mediated serine transport from the cytosol to the mitochondria. Loss of SERAC1 impaired the one-carbon cycle and disrupted the balance of the nucleotide pool, which led to primary mitochondrial DNA (mtDNA) depletion in mice, HEK293T cells, and patient-derived immortalized lymphocyte cells due to insufficient supply of nucleotides. Moreover, both in vitro and in vivo supplementation of nucleosides/nucleotides restored mtDNA content and mitochondrial function. Collectively, our findings suggest that MEGD(H)EL syndrome shares both clinical and molecular features with the mtDNA depletion syndrome, and nucleotide supplementation may be an effective therapeutic strategy for MEGD(H)EL syndrome.
    DOI:  https://doi.org/10.1126/scitranslmed.abl6992
  10. Ren Fail. 2022 Dec;44(1): 358-367
    Peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) overexpression alleviates endoplasmic reticulum stress after acute kidney injury.
    Hao Pan, Zhizhi Hu, Zhongwen Shao, Yong Ning.
       BACKGROUND: Mitochondrial biogenesis dysregulation and enhanced endoplasmic reticulum (ER) stress have been implicated in the progression of acute kidney injury (AKI). However, the interaction between these two events remains poorly understood. This study was designed to investigate the role of peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) expression, a key factor in mitochondrial biogenesis, in renal ER stress at 24 h after AKI and the underlying mechanisms.
    METHODS: Mice were administered recombinant adenovirus encoding murine PGC-1α (100 μl, 1.0 × 109PFU/ml) or vehicle five days before renal ischemia reperfusion (I/R) or sham operation. Twenty-four hours after the operation, kidney and serum samples were collected for evaluation.
    RESULTS: We first confirmed that PGC-1α transfection elevated the PGC-1α levels and mitochondrial transcripts in the kidney 24 h after AKI. Then, we found PGC-1α overexpression improved renal function. PGC-1α transfection inhibited AKI-induced ER stress through the unfolded protein response (UPR) pathway, resulting in the suppression of apoptosis via both mitochondrial and ER pathways. Further study showed that the expression of mitofusin 2 (Mfn2), an interaction protein between mitochondria and ER, was increased after PGC-1α overexpression. We also found the expression of a novel ER stress regulator, hairy and enhancer of split 1 (Hes1), was decreased after PGC-1α transfection.
    CONCLUSIONS: Our findings reveal that mitochondrial biogenesis plays an important role in the progression of AKI-induced ER stress and provide useful evidence for research on organelle crosstalk during AKI.
    Keywords:  PGC-1α; acute kidney injury; endoplasmic reticulum stress
    DOI:  https://doi.org/10.1080/0886022X.2022.2035764
  11. Front Pharmacol. 2022 ;13 819787
    Atorvastatin Restores PPARα Inhibition of Lipid Metabolism Disorders by Downregulating miR-21 Expression to Improve Mitochondrial Function and Alleviate Diabetic Nephropathy Progression.
    Jiayi Xiang, Huifang Zhang, Xingcheng Zhou, Dan Wang, Rongyu Chen, Wanlin Tan, Luqun Liang, Mingjun Shi, Fan Zhang, Ying Xiao, Yuxia Zhou, Yuanyuan Wang, Bing Guo.
      Atorvastatin is a classical lipid-lowering drug. It has been reported to have renoprotective effects, such as reducing urinary protein excretion and extracellular matrix aggregation. The present study aimed to investigate the specific mechanism of action of Atorvastatin in type 1 diabetic mice (T1DM) in inhibiting renal tubular epithelial cell injury following treatment with high glucose and high fat. The anti-injury mechanism of Atorvastatin involved the inhibition of miR-21 expression and the upregulation of the transcription and expression of its downstream gene Peroxisome proliferator-activated receptors-α(PPARα). An increase in blood glucose and lipid levels was noted in the T1DM model, which was associated with renal fibrosis and inflammation. These changes were accompanied by increased miR-21 levels, downregulation of PPARα and Mfn1 expressions, and upregulation of Drp1 and IL6 expressions in renal tissues. These phenomena were reversed following the administration of Atorvastatin. miR-21 targeted PPARα by inhibiting its mRNA translation. Inhibition of miR-21 expression or Fenofibrate (PPARα agonist) administration prevented the decrease of PPARα in renal tubular epithelial cells under high glucose (HG) and high fat (Palmitic acid, PA) conditions, alleviating lipid metabolism disorders and reducing mitochondrial dynamics and inflammation. Consistent with the in vivo results, the in vitro findings also demonstrated that mRTECs administered with Atorvastatin in HG + PA increased PPARα expression and restored the normal expression of Mfn1 and Drp1, and effectively increasing the number of biologically active mitochondria and ATP content, reducing ROS production, and restoring mitochondrial membrane potential following Atorvastatin intervention. In addition, these effects were noted to the inhibition of FN expression and tubular cell inflammatory response; however, in the presence of miR-21mimics, the aforementioned effects of Atorvastatin were significantly diminished. Based on these observations, we conclude that Atorvastatin inhibits tubular epithelial cell injury in T1DM with concomitant induction of lipid metabolism disorders by a mechanism involving inhibition of miR-21 expression and consequent upregulation of PPARα expression. Moreover, Atorvastatin regulated lipid metabolism homeostasis and PPARα to restore mitochondrial function. The results emphasize the potential of Atorvastatin to exhibit lipid-regulating functions and non-lipid effects that balance mitochondrial dynamics.
    Keywords:  PPARα; atorvastatin; diabetic kidney disease; fenofibrate; lipid metabolism disorders; miR-21; mitochondrial dynamics
    DOI:  https://doi.org/10.3389/fphar.2022.819787
  12. Mol Cell. 2022 Mar 03. pii: S1097-2765(22)00108-3. [Epub ahead of print]82(5): 1066-1077.e7
    MFN2-driven mitochondria-to-nucleus tethering allows a non-canonical nuclear entry pathway of the mitochondrial pyruvate dehydrogenase complex.
    Sotirios D Zervopoulos, Aristeidis E Boukouris, Bruno Saleme, Alois Haromy, Saymon Tejay, Gopinath Sutendra, Evangelos D Michelakis.
      The mitochondrial pyruvate dehydrogenase complex (PDC) translocates into the nucleus, facilitating histone acetylation by producing acetyl-CoA. We describe a noncanonical pathway for nuclear PDC (nPDC) import that does not involve nuclear pore complexes (NPCs). Mitochondria cluster around the nucleus in response to proliferative stimuli and tether onto the nuclear envelope (NE) via mitofusin-2 (MFN2)-enriched contact points. A decrease in nuclear MFN2 levels decreases mitochondria tethering and nPDC levels. Mitochondrial PDC crosses the NE and interacts with lamin A, forming a ring below the NE before crossing through the lamin layer into the nucleoplasm, in areas away from NPCs. Effective blockage of NPC trafficking does not decrease nPDC levels. The PDC-lamin interaction is maintained during cell division, when lamin depolymerizes and disassembles before reforming daughter nuclear envelopes, providing another pathway for nPDC entry during mitosis. Our work provides a different angle to understanding mitochondria-to-nucleus communication and nuclear metabolism.
    Keywords:  acetylation; cell cycle; lamin; metabolism; mitochondria; mitofusin; nucleus; protein trafficking; pyruvate dehydrogenase complex; tethering
    DOI:  https://doi.org/10.1016/j.molcel.2022.02.003
  13. ACS Sens. 2022 Feb 28.
    Ratiometric Imaging of Mitochondrial Hydrogen Peroxide in Aβ42-Mediated Neurotoxicity.
    Xinyu Li, Yiyu Zhang, Hui-Wang Ai.
      Oxidative stress is important for the etiology and pathogenesis of Alzheimer's disease (AD). Research tools that can conveniently evaluate oxidative stress in AD models are expected to catalyze and accelerate research on AD. This study explored the use of genetically encoded fluorescent indicators (GEFIs) to detect mitochondrial oxidative stress in organotypic brain slices and AD mouse models. To enable ratiometric normalization and avoid tissue autofluorescence, we genetically fused a green fluorescent hydrogen peroxide (H2O2) indicator, HyPer7, with each of two selected, bright red fluorescent proteins (RFPs), mScarlet-I and tdTomato. The resultant indicators, namely, HyPerGRS and HyPerGRT, were tagged with mitochondrial targeting sequences and examined for localization and function in cultured HeLa cells and primary mouse neurons. We further utilized HyPerGRT, which is a genetic fusion of HyPer7 with tdTomato, to monitor mitochondrial H2O2 in response to the human β-amyloid 1-42 isoform (Aβ42) in cultured brain slices and an AD mouse model. Owing to the high sensitivity and low autofluorescence interference resulting from HyPerGRT, we successfully detected Aβ42-mediated mitochondrial H2O2 in these AD models. The results suggest that HyPerGRT is a valuable tool for studying mitochondrial oxidative stress in tissues and animals.
    Keywords:  Alzheimer’s disease; fluorescent proteins; genetically encoded fluorescent indicators; oxidative stress; ratiometric imaging
    DOI:  https://doi.org/10.1021/acssensors.1c01381
  14. PLoS Biol. 2022 Mar;20(3): e3001380
    The ER membrane complex (EMC) can functionally replace the Oxa1 insertase in mitochondria.
    Büsra Güngör, Tamara Flohr, Sriram G Garg, Johannes M Herrmann.
      Two multisubunit protein complexes for membrane protein insertion were recently identified in the endoplasmic reticulum (ER): the guided entry of tail anchor proteins (GET) complex and ER membrane complex (EMC). The structures of both of their hydrophobic core subunits, which are required for the insertion reaction, revealed an overall similarity to the YidC/Oxa1/Alb3 family members found in bacteria, mitochondria, and chloroplasts. This suggests that these membrane insertion machineries all share a common ancestry. To test whether these ER proteins can functionally replace Oxa1 in yeast mitochondria, we generated strains that express mitochondria-targeted Get2-Get1 and Emc6-Emc3 fusion proteins in Oxa1 deletion mutants. Interestingly, the Emc6-Emc3 fusion was able to complement an Δoxa1 mutant and restored its respiratory competence. The Emc6-Emc3 fusion promoted the insertion of the mitochondrially encoded protein Cox2, as well as of nuclear encoded inner membrane proteins, although was not able to facilitate the assembly of the Atp9 ring. Our observations indicate that protein insertion into the ER is functionally conserved to the insertion mechanism in bacteria and mitochondria and adheres to similar topological principles.
    DOI:  https://doi.org/10.1371/journal.pbio.3001380
  15. J Biochem Mol Toxicol. 2022 Mar 03. e23032
    Renoprotective potential of myo-inositol on diabetic kidney disease: Focus on the role of the PINK1/Parkin pathway and mitophagy receptors.
    Bhoomika Sherkhane, Anil Kumar Kalvala, Vijay Kumar Arruri, Dharmendra Kumar Khatri, Shashi Bala Singh.
      Recent studies have emphasized the role of mitochondria in renal function as well as in renal injury. Poor mitochondrial quality control mechanisms including mitochondrial fusion, fission and mitophagy are major contributors for progression of diabetic renal injury. The current study is aimed to evaluate the protective role of myo-inositol (MI) against diabetic nephropathy (DN) by utilizing high glucose exposed NRK 52E cell and streptozotocin (STZ) induced DN model. MI supplementation (at doses 37.5 and 75 mg/kg) ameliorated albuminuria and enhanced the renal function as indicated significant improvement in urinary creatinine and urea levels. On the other hand, the western blot analysis of both in vitro and in vivo studies has revealed poor mitophagy in renal cells which was reversed upon myo-inositol treatment. Apart from targeting the canonical PINK1/Parkin pathway, we also focused on the role mitophagy receptors prohibitin (PHB) and NIP3-like protein (NIX). A significant reduction in expression of NIX and PHB2 was observed in renal tissue of diabetic control rats and high glucose exposed NRK 52E cells. Myo-inositol treatment resulted in positive modulation of PINK1/Parkin pathway as well as PHB2 and NIX. Myo-inositol also enhanced the mitochondrial biogenesis in renal tissue of diabetic rat by upregulating Nrf2/SIRT1/PGC-1α axis. The current study thus underlines the renoprotective effect myo-inositol, upregulation of mitophagy proteins and mitochondrial biogenesis upon myo-inositol treatment.
    Keywords:  Myo-inositol; NIX; PINK1; ParKin; diabetic nephropathy; mitophagy; prohibtin
    DOI:  https://doi.org/10.1002/jbt.23032
  16. Biomed Res Int. 2022 ;2022 7436577
    Mitochondrial ROS Produced by Skeletal Muscle Mitochondria Promote the Decisive Signal for UPRmt Activation.
    Zhe Wang, Hai Bo, Yu Song, Can Li, Yong Zhang.
      The mitochondrial unfolded protein response (UPRmt) can repair and remove misfolded or unfolded proteins in mitochondria and enhance mitochondrial protein homeostasis. Reactive oxygen species (ROS) produced by regular exercise is a crucial signal for promoting health, and skeletal muscle mitochondria are the primary source of ROS during exercise. To verify whether UPRmt is related to ROS produced by mitochondria in skeletal muscle during regular exercise, we adapted MitoTEMPO, mitochondrially targeted antioxidants, and ROS production by mitochondria. Our results showed that mitochondrial ROS is the key factor for activating UPRmt in different pathways.
    DOI:  https://doi.org/10.1155/2022/7436577
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