bims-mecmid Biomed News
on Membrane communication in mitochondrial dynamics
Issue of 2022–05–08
sixteen papers selected by
Mauricio Cardenas Rodriguez, University of Padova
  1. The role of mitochondrial fission in cardiovascular health and disease.
  2. Moxibustion alleviates chronic heart failure by regulating mitochondrial dynamics and inhibiting autophagy.
  3. Modulation of Mitochondrial Dynamics Rescues Cognitive Function in Rats with "Doxorubicin-Induced Chemobrain" via Mitigation of Mitochondrial Dysfunction and Neuroinflammation.
  4. Prognostic significance of dynamin-related protein 1 expression in advanced lung adenocarcinoma.
  5. Inhibition of Drp1 ameliorates diabetic retinopathy by regulating mitochondrial homeostasis.
  6. High-content high-throughput imaging reveals distinct connections between mitochondrial morphology and functionality for OXPHOS complex I, III, and V inhibitors.
  7. Mechanistic insights into fungal mitochondrial outer membrane protein biogenesis.
  8. RAGE Regulating Vascular Remodeling in Diabetes by Regulating Mitochondrial Dynamics with JAK2/STAT3 Pathway.
  9. MFN2 Deficiency Impairs Mitochondrial Functions and PPAR Pathway During Spermatogenesis and Meiosis in Mice.
  10. Protein import in mitochondria biogenesis: guided by targeting signals and sustained by dedicated chaperones.
  11. The MFN1 and MFN2 mitofusins promote clustering between mitochondria and peroxisomes.
  12. VAMP8 phosphorylation regulates lysosome dynamics during autophagy.
  13. Erratum for Cadena et al., "Mitochondrial Contact Site and Cristae Organization System and F1FO-ATP Synthase Crosstalk Is a Fundamental Property of Mitochondrial Cristae".
  14. Protein-protein and protein-lipid interactions of pore-forming BCL-2 family proteins in apoptosis initiation.
  15. Photoreceptor Manifestations of Primary Mitochondrial Optic Nerve Disorders.
  16. The mitoXplorer 2.0 update: integrating and interpreting mitochondrial expression dynamics within a cellular context.
  1. Nat Rev Cardiol. 2022 May 06.
    The role of mitochondrial fission in cardiovascular health and disease.
    Justin M Quiles, Åsa B Gustafsson.
      Mitochondria are organelles involved in the regulation of various important cellular processes, ranging from ATP generation to immune activation. A healthy mitochondrial network is essential for cardiovascular function and adaptation to pathological stressors. Mitochondria undergo fission or fusion in response to various environmental cues, and these dynamic changes are vital for mitochondrial function and health. In particular, mitochondrial fission is closely coordinated with the cell cycle and is linked to changes in mitochondrial respiration and membrane permeability. Another key function of fission is the segregation of damaged mitochondrial components for degradation by mitochondrial autophagy (mitophagy). Mitochondrial fission is induced by the large GTPase dynamin-related protein 1 (DRP1) and is subject to sophisticated regulation. Activation requires various post-translational modifications of DRP1, actin polymerization and the involvement of other organelles such as the endoplasmic reticulum, Golgi apparatus and lysosomes. A decrease in mitochondrial fusion can also shift the balance towards mitochondrial fission. Although mitochondrial fission is necessary for cellular homeostasis, this process is often aberrantly activated in cardiovascular disease. Indeed, strong evidence exists that abnormal mitochondrial fission directly contributes to disease development. In this Review, we compare the physiological and pathophysiological roles of mitochondrial fission and discuss the therapeutic potential of preventing excessive mitochondrial fission in the heart and vasculature.
    DOI:  https://doi.org/10.1038/s41569-022-00703-y
  2. Exp Ther Med. 2022 May;23(5): 359
    Moxibustion alleviates chronic heart failure by regulating mitochondrial dynamics and inhibiting autophagy.
    Ran Xia, Wei Wang, Bing Gao, Qiang Ma, Jing Wang, Xiaohua Dai, Qingling Li.
      Moxibustion (MOX) is a traditional Chinese medicine preparation, which has been clinically used to treat cardiac diseases in recent years. The present study aimed to examine the protective effects and possible mechanisms of MOX on doxorubicin (DOX)-induced chronic heart failure (CHF) in rats. The animals were divided into five groups, including the Control (normal saline), DOX (doxorubicin 15 mg/kg), MOX (doxorubicin 15 mg/kg + moxibustion), BEN (doxorubicin 15 mg/kg + benazepril 0.86 mg/kg) and MOX + BEN (doxorubicin 15 mg/kg + moxibustion + benazepril 0.86 mg/kg) groups. After three weeks, echocardiography was performed to assess cardiac function and structure, including left ventricular internal diameter in systole, ejection fraction and fractional shortening (FS). Serum brain natriuretic peptide levels and adenosine triphosphate (ATP) levels were measured by enzyme-linked immunosorbent assay and ATP assay. Cardiac pathology was assessed by hematoxylin and eosin and Masson's trichrome staining. Cardiac ultrastructure and the number of autophagosomes formed were visualized by transmission electron microscopy. Western blotting was performed to assess mitochondrial dynamics, autophagy proteins and mitochondrial autophagy-related pathway proteins. The expression levels of these genes were assessed by reverse transcription-quantitative PCR. The results indicated MOX could improve cardiac function, increased cardiac ATP levels and reduced myocardial fibrosis. Western blotting indicated that MOX treatment elevated the expression of optic atrophy 1 protein (OPA1), while decreasing the expression of dynamin-related protein 1 and mitochondrial fission 1 protein. In addition, MOX inhibited autophagy, as evidenced by decreased number of autophagosomes, reduced LC3II/LC3I ratio and increased p62 expression. Furthermore, MOX downregulated DOX-induced FUNDC1 signaling pathway. In summary, MOX has protective effects on DOX-induced CHF in rats, promoting mitochondrial fusion while inhibiting mitochondrial fission and mitophagy. The underlying mechanisms may be related to the inhibition of the FUNDC1 signaling pathway.
    Keywords:  chronic heart failure; mitochondrial fission; mitochondrial fusion; mitophagy; moxibustion; pathway
    DOI:  https://doi.org/10.3892/etm.2022.11286
  3. FEBS J. 2022 May 05.
    Modulation of Mitochondrial Dynamics Rescues Cognitive Function in Rats with "Doxorubicin-Induced Chemobrain" via Mitigation of Mitochondrial Dysfunction and Neuroinflammation.
    Benjamin Ongnok, Chayodom Maneechote, Titikorn Chunchai, Patcharapong Pantiya, Busarin Arunsak, Wichwara Nawara, Nipon Chattipakorn, Siriporn C Chattipakorn.
      Doxorubicin (DOX), an effective, extensively used chemotherapeutic drug, can cause cognitive deterioration in cancer patients. The associated debilitating neurological sequelae are referred to as chemobrain. Our recent work demonstrated that Dox treatment resulted in an imbalance in mitochondrial dynamics ultimately culminating in cognitive decline in rats. Therefore, in this study we aim to explore the therapeutic efficacy of a pharmacological intervention which modulates mitochondrial dynamics using a potent mitochondrial fission inhibitor (Mdivi-1) and mitochondrial fusion promoter (M1) against Dox-induced chemobrain. In the study, male Wistar rats were randomly assigned to receive either normal saline solution or 6 doses of Dox (3 mg/kg) via intraperitoneal injection. Then, the Dox-treated rats were intraperitoneally given either 1% DMSO as the vehicle, Mdivi-1 (1.2 mg/kg), M1 (2 mg/kg), or a combined treatment of Mdivi-1 and M1 for 30 consecutive days. Long-term learning and memory were evaluated using the novel object location task and novel object recognition task. Following euthanasia, the rat brains were dissected to enable further molecular investigation. We demonstrated that long-term treatment with mitochondrial dynamic modulators suppressed mitochondrial fission in the hippocampus following Dox treatment, leading to an improvement in brain homeostasis. Mitochondrial dynamic modulator treatments restored cognitive function in Dox-treated rats by attenuating neuroinflammation, decreasing oxidative stress, preserving synaptic integrity, reducing potential Alzheimer's-related lesions, and mitigating both apoptosis and necroptosis following Dox administration. Together, our findings suggested that mitochondrial dynamics modulators protected against Dox-induced cognitive impairment by rebalancing mitochondrial homeostasis and attenuating both oxidative and inflammatory insults.
    Keywords:  Chemobrain; Chemotherapy; Doxorubicin; Mitochondrial dynamic modulator; Mitochondrial dynamics
    DOI:  https://doi.org/10.1111/febs.16474
  4. Pathol Res Pract. 2022 Apr 29. pii: S0344-0338(22)00175-3. [Epub ahead of print]234 153931
    Prognostic significance of dynamin-related protein 1 expression in advanced lung adenocarcinoma.
    Yen-Lin Huang, Yi-Jung Chen, Yi-Hsiu Juan, Shang-Gin Wu, Kuei-Pin Chung.
       BACKGROUND: Dynamin-related protein 1 (DRP1) is a key regulator of mitochondrial fission and is activated by phosphorylation at serine 616. We previously demonstrated that DRP1 activation is regulated by epidermal growth factor receptor (EGFR) signaling and multiple kinases in lung adenocarcinoma, and is significantly associated with an increased risk of postoperative recurrence in early stage lung adenocarcinoma. However, it is unclear whether DRP1 activation is associated with worse prognosis in patients with advanced lung adenocarcinoma. This study is aimed to examine whether P(S616)-DRP1 expression is significantly related to the survival of patients with advanced lung adenocarcinoma.
    MATERIALS AND METHODS: Biopsy samples were obtained from patients with stage IV lung adenocarcinoma. The activation status of DRP1 in cancer cells was quantified based on the immunohistochemical stain of phosphorylated DRP1 at serine 616 [P(S616)-DRP1]. Results of EGFR, ALK, ROS1, and KRAS mutations were retrieved from the medical records. The staining intensity and the histological scores (H-scores) of P(S616)-DRP1 were analyzed for association with progression-free survival (PFS) under first-line tyrosine-kinase inhibitors (TKIs) and with overall survival (OS).
    RESULTS: Overall, 123 patients with stage IV lung adenocarcinoma constituted the study population, and 90 (73.2%) patients received TKIs as the first-line treatments. The median P(S616)-DRP1H-score was used to dichotomize the study population into the high (n = 61) and low (n = 62) DRP1 activation groups. DRP1 was significantly less phosphorylated in lung adenocarcinoma with EGFR, ALK, ROS1, and KRAS mutations. Importantly, in patients who received first-line TKIs, DRP1 phosphorylation was not significantly correlated with PFS and OS. Multivariate Cox proportional hazard models showed that high DRP1 activation in cancer cells was not significantly associated with worse OS in the study population (adjusted hazard ratio: 1.402, 95% confidence interval: 0.865-2.271, p = 0.170). Similar results were obtained in the analysis based on the intensities of P(S616)-DRP1 in cancer cells.
    CONCLUSIONS: Our data demonstrate that DRP1 phosphorylation is not related to the prognosis of patients with advanced lung adenocarcinoma.
    Keywords:  Dynamin-related protein 1; Epidermal growth factor receptor; Lung adenocarcinoma; Mitochondria; Survival
    DOI:  https://doi.org/10.1016/j.prp.2022.153931
  5. Exp Eye Res. 2022 Apr 28. pii: S0014-4835(22)00175-0. [Epub ahead of print] 109095
    Inhibition of Drp1 ameliorates diabetic retinopathy by regulating mitochondrial homeostasis.
    Meng-Yuan Zhang, Lingpeng Zhu, Xun Bao, Tian-Hua Xie, Jiping Cai, Jian Zou, Wenjuan Wang, Shun Gu, Yan Li, Hong-Ying Li, Yong Yao, Ting-Ting Wei.
      Diabetic retinopathy (DR) is a potentially blinding complication resulting from diabetes mellitus (DM). Retinal vascular endothelial cells (RMECs) dysfunction occupies an important position in the pathogenesis of DR, and mitochondrial disorders play a vital role in RMECs dysfunction. However, the detailed mechanisms underlying DR-induced mitochondrial disorders in RMECs remain elusive. In the present study, we used High glucose (HG)-induced RMECs in vitro and streptozotocin (STZ)-induced Sprague-Dawley rats in vivo to explore the related mechanisms. We found that HG-induced mitochondrial dysfunction via mitochondrial Dynamin-related protein 1(Drp1)-mediated mitochondrial fission. Drp1 inhibitor, Mdivi-1, rescued HG-induced mitochondrial dysfunction. Protein Kinase Cδ (PKCδ) could induce phosphorylation of Drp1, and we found that HG induced phosphorylation of PKCδ. PKCδ inhibitor (Go 6983) or PKCδ siRNA reversed HG-induced phosphorylation of Drp1 and further mitochondrial dysfunction. The above studies indicated that HG increases mitochondrial fission via promoting PKCδ/Drp1 signaling. Drp1 induces excessive mitochondrial fission and produces damaged mitochondrial, and mitophagy plays a key role in clearing damaged mitochondrial. Our study showed that HG suppressed mitophagy via inhibiting LC3B-II formation and p62 degradation. 3-MA (autophagy inhibitor) aggravated HG-induced RMECs damage, while rapamycin (autophagy agonist) rescued the above phenomenon. Further studies were identified that HG inhibited mitophagy by down-regulation of the PINK1/Parkin signaling pathway, and PINK1 siRNA aggravated HG-induced RMECs damage. Further in-depth study, we propose that Drp1 promotion of Hexokinase II (HK-II) separation from mitochondria, thus inhibiting HK-II-PINK1-mediated mitophagy. In vivo, we found that intraretinal microvascular abnormalities (IRMA), including retinal vascular leakage, acellular capillaries, and apoptosis were increased in STZ-induced DR rats, which were reversed by pretreatment with Mdivi-1 or Rapamycin. Altogether, our findings provide new insight into the mechanisms underlying the regulation of mitochondrial homeostasis and provide a potential treatment strategy for Diabetic retinopathy.
    Keywords:  Diabetic retinopathy; Drp1; Mitochondrial fission; Mitophagy; PINK1
    DOI:  https://doi.org/10.1016/j.exer.2022.109095
  6. Cell Biol Toxicol. 2022 May 04.
    High-content high-throughput imaging reveals distinct connections between mitochondrial morphology and functionality for OXPHOS complex I, III, and V inhibitors.
    Wanda van der Stel, Huan Yang, Sylvia E le Dévédec, Bob van de Water, Joost B Beltman, Erik H J Danen.
      Cells can adjust their mitochondrial morphology by altering the balance between mitochondrial fission and fusion to adapt to stressful conditions. The connection between a chemical perturbation, changes in mitochondrial function, and altered mitochondrial morphology is not well understood. Here, we made use of high-throughput high-content confocal microscopy to assess the effects of distinct classes of oxidative phosphorylation (OXPHOS) complex inhibitors on mitochondrial parameters in a concentration and time resolved manner. Mitochondrial morphology phenotypes were clustered based on machine learning algorithms and mitochondrial integrity patterns were mapped. In parallel, changes in mitochondrial membrane potential (MMP), mitochondrial and cellular ATP levels, and viability were microscopically assessed. We found that inhibition of MMP, mitochondrial ATP production, and oxygen consumption rate (OCR) using sublethal concentrations of complex I and III inhibitors did not trigger mitochondrial fragmentation. Instead, complex V inhibitors that suppressed ATP and OCR but increased MMP provoked a more fragmented mitochondrial morphology. In agreement, complex V but not complex I or III inhibitors triggered proteolytic cleavage of the mitochondrial fusion protein, OPA1. The relation between increased MMP and fragmentation did not extend beyond OXPHOS complex inhibitors: increasing MMP by blocking the mPTP pore did not lead to OPA1 cleavage or mitochondrial fragmentation and the OXPHOS uncoupler FCCP was associated with OPA1 cleavage and MMP reduction. Altogether, our findings connect vital mitochondrial functions and phenotypes in a high-throughput high-content confocal microscopy approach that help understanding of chemical-induced toxicity caused by OXPHOS complex perturbing chemicals.
    Keywords:  ATP; Machine learning; Membrane potential; Mitochondria; Morphology
    DOI:  https://doi.org/10.1007/s10565-022-09712-6
  7. Curr Opin Struct Biol. 2022 Apr 30. pii: S0959-440X(22)00062-8. [Epub ahead of print]74 102383
    Mechanistic insights into fungal mitochondrial outer membrane protein biogenesis.
    Kathryn A Diederichs, Ashley S Pitt, Joyce T Varughese, Taylor N Hackel, Susan K Buchanan, Porsha L Shaw.
      The majority of mitochondrial proteins are nuclear-encoded and need to be transported into the mitochondria, including the proteins in the outer mitochondrial membrane. For β-barrel proteins, the preproteins are initially recognized and imported by the TOM complex, then shuttled to the SAM complex via small Tim proteins. For ⍺-helical proteins, some preproteins are recognized by the TOM complex and imported into the membrane by the MIM complex. In recent years multiple structures of the TOM complex and the SAM complex have been reported, increasing our understanding of the mechanism of protein biogenesis in the outer mitochondrial membrane.
    DOI:  https://doi.org/10.1016/j.sbi.2022.102383
  8. Comput Intell Neurosci. 2022 ;2022 2685648
    RAGE Regulating Vascular Remodeling in Diabetes by Regulating Mitochondrial Dynamics with JAK2/STAT3 Pathway.
    Shengjia Sun, Qiying Chen, Bangwei Wu, Qingyu Huang, Alimujiang Maimaitijiang.
      In this research, we will explore the role and modulation of mitochondrial dynamics in diabetes vascular remodeling. Only a few cell types express the pattern recognition receptor, also known as the AGE receptor (RAGE). However, it is triggered in almost all of the cells that have been investigated thus far by events that are known to cause inflammation. Here, Type 2 diabetes was studied in both cellular and animal models. Elevated Receptor for advanced glycation end products (RAGE), phosphorylated JAK2 (p-JAK2), phosphorylated STAT3 (p-STAT3), transient receptor potential ion channels (TRPM), and phosphorylated dynamin-related protein 1 (p-DRP1) were observed in the context of diabetes. In addition, we found that inhibition of RAGE was followed by a remarkable decrease in the expression of the above proteins. It has also been demonstrated by western blotting and immunofluorescence results in vivo and in vitro. Suppressing STAT3 and DRP1 phosphorylation produced effects similar to those of RAGE inhibition on the proliferation, cell cycle, migration, invasion, and expression of TRPM in VSMCs and vascular tissues obtained from diabetic animals. These findings indicate that RAGE regulates vascular remodeling via mitochondrial dynamics through modulating the JAK2/STAT3 axis in diabetes. The findings could be crucial in gaining a better understanding of diabetes-related vascular remodeling. It also contributes to a better cytopathological understanding of diabetic vascular disease and provides a theoretical foundation for novel targets that aid in the prevention and treatment of diabetes-related cardiovascular problems.
    DOI:  https://doi.org/10.1155/2022/2685648
  9. Front Cell Dev Biol. 2022 ;10 862506
    MFN2 Deficiency Impairs Mitochondrial Functions and PPAR Pathway During Spermatogenesis and Meiosis in Mice.
    Tianren Wang, Yuan Xiao, Zhe Hu, Jingkai Gu, Renwu Hua, Zhuo Hai, Xueli Chen, Jian V Zhang, Zhiying Yu, Ting Wu, William S B Yeung, Kui Liu, Chenxi Guo.
      Mitochondria are highly dynamic organelles and their activity is known to be regulated by changes in morphology via fusion and fission events. However, the role of mitochondrial dynamics on cellular differentiation remains largely unknown. Here, we explored the molecular mechanism of mitochondrial fusion during spermatogenesis by generating an Mfn2 (mitofusin 2) conditional knock-out (cKO) mouse model. We found that depletion of MFN2 in male germ cells led to disrupted spermatogenesis and meiosis during which the majority of Mfn2 cKO spermatocytes did not develop to the pachytene stage. We showed that in these Mfn2 cKO spermatocytes, oxidative phosphorylation in the mitochondria was affected. In addition, RNA-Seq analysis showed that there was a significantly altered transcriptome profile in the Mfn2 deficient pachytene (or pachytene-like) spermatocytes, with a total of 262 genes up-regulated and 728 genes down-regulated, compared with wild-type (control) mice. Pathway enrichment analysis indicated that the peroxisome proliferator-activated receptor (PPAR) pathway was altered, and subsequent more detailed analysis showed that the expression of PPAR α and PPAR γ was up-regulated and down-regulated, respectively, in the MFN2 deficient pachytene (or pachytene-like) spermatocytes. We also demonstrated that there were more lipid droplets in the Mfn2 cKO cells than in the control cells. In conclusion, our study demonstrates a novel finding that MFN2 deficiency negatively affects mitochondrial functions and alters PPAR pathway together with lipid metabolism during spermatogenesis and meiosis.
    Keywords:  lipid metabolism; meiosis; mitochondrial dynamics; mitofusin 2; spermatogenesis
    DOI:  https://doi.org/10.3389/fcell.2022.862506
  10. RSC Adv. 2021 Sep 27. 11(51): 32476-32493
    Protein import in mitochondria biogenesis: guided by targeting signals and sustained by dedicated chaperones.
    Anna-Roza Dimogkioka, Jamie Lees, Erik Lacko, Kostas Tokatlidis.
      Mitochondria have a central role in cellular metabolism; they are responsible for the biosynthesis of amino acids, lipids, iron-sulphur clusters and regulate apoptosis. About 99% of mitochondrial proteins are encoded by nuclear genes, so the biogenesis of mitochondria heavily depends on protein import pathways into the organelle. An intricate system of well-studied import machinery facilitates the import of mitochondrial proteins. In addition, folding of the newly synthesized proteins takes place in a busy environment. A system of folding helper proteins, molecular chaperones and co-chaperones, are present to maintain proper conformation and thus avoid protein aggregation and premature damage. The components of the import machinery are well characterised, but the targeting signals and how they are recognised and decoded remains in some cases unclear. Here we provide some detail on the types of targeting signals involved in the protein import process. Furthermore, we discuss the very elaborate chaperone systems of the intermembrane space that are needed to overcome the particular challenges for the folding process in this compartment. The mechanisms that sustain productive folding in the face of aggregation and damage in mitochondria are critical components of the stress response and play an important role in cell homeostasis.
    DOI:  https://doi.org/10.1039/d1ra04497d
  11. Commun Biol. 2022 May 06. 5(1): 423
    The MFN1 and MFN2 mitofusins promote clustering between mitochondria and peroxisomes.
    Yinbo Huo, Weiping Sun, Tiezhu Shi, Song Gao, Min Zhuang.
      Mitochondria and peroxisomes are two types of functionally close-related organelles, and both play essential roles in lipid and ROS metabolism. However, how they physically interact with each other is not well understood. In this study, we apply the proximity labeling method with peroxisomal proteins and report that mitochondrial protein mitofusins (MFNs) are in proximity to peroxisomes. Overexpression of MFNs induces not only the mitochondria clustering but also the co-clustering of peroxisomes. We also report the enrichment of MFNs at the mitochondria-peroxisome interface. Induced mitofusin expression gives rise to more mitochondria-peroxisome contacting sites. Furthermore, the tethering of peroxisomes to mitochondria can be inhibited by the expression of a truncated MFN2, which lacks the transmembrane region. Collectively, our study suggests MFNs as regulators for mitochondria-peroxisome contacts. Our findings are essential for future studies of inter-organelle metabolism regulation and signaling, and may help understand the pathogenesis of mitofusin dysfunction-related disease.
    DOI:  https://doi.org/10.1038/s42003-022-03377-x
  12. Autophagy Rep. 2022 ;1(1): 79-82
    VAMP8 phosphorylation regulates lysosome dynamics during autophagy.
    Lei Wang, Jiajie Diao.
      In the final critical step for autophagic degradation, lysosomes fuse with autophagosomes to form autolysosomes. Although recent research has suggested that soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins are important for lysosome-autophagosome fusion, neither the architecture of the prefusion state nor the regulatory mechanisms have been identified. In our study, using structured illumination microscopy, we observed that lysosomes formed clusters around individual autophagosomes, thereby setting the stage for membrane fusion. Moreover, VAMP8 (vesicle-associated membrane protein 8) assists in forming the prefusion state of these clusters. We also found that VAMP8 phosphorylation reduces spontaneous lysosome-autophagosome fusion, whereas its dephosphorylation promotes fusion events between lysosomes and autophagosomes in both normal and autophagy-induced conditions. Our data thus suggest a key role of VAMP8 phosphorylation in the regulation of lysosome-autophagosome fusion.
    Keywords:  Autophagy; VAMP8; fusion; lysosomes; phosphorylation
    DOI:  https://doi.org/10.1080/27694127.2022.2031378
  13. mSphere. 2022 May 02. e0018922
    Erratum for Cadena et al., "Mitochondrial Contact Site and Cristae Organization System and F1FO-ATP Synthase Crosstalk Is a Fundamental Property of Mitochondrial Cristae".
    Lawrence Rudy Cadena, Ondřej Gahura, Brian Panicucci, Alena Zíková, Hassan Hashimi.
      
    DOI:  https://doi.org/10.1128/msphere.00189-22
  14. Biochem Soc Trans. 2022 May 06. pii: BST20220323. [Epub ahead of print]
    Protein-protein and protein-lipid interactions of pore-forming BCL-2 family proteins in apoptosis initiation.
    Giridhar Sekar, Adedolapo Ojoawo, Tudor Moldoveanu.
      Apoptosis is a common cell death program that is important in human health and disease. Signaling in apoptosis is largely driven through protein-protein interactions. The BCL-2 family proteins function in protein-protein interactions as key regulators of mitochondrial poration, the process that initiates apoptosis through the release of cytochrome c, which activates the apoptotic caspase cascade leading to cellular demolition. The BCL-2 pore-forming proteins BAK and BAX are the key executors of mitochondrial poration. We review the state of knowledge of protein-protein and protein-lipid interactions governing the apoptotic function of BAK and BAX, as determined through X-ray crystallography and NMR spectroscopy studies. BAK and BAX are dormant, globular α-helical proteins that participate in protein-protein interactions with other pro-death BCL-2 family proteins, transforming them into active, partially unfolded proteins that dimerize and associate with and permeabilize mitochondrial membranes. We compare the protein-protein interactions observed in high-resolution structures with those derived in silico by AlphaFold, making predictions based on combining experimental and in silico approaches to delineate the structural basis for novel protein-protein interaction complexes of BCL-2 family proteins.
    Keywords:  alphafold; apoptosis initiation; crystallography; mitochondrial poration; pore-forming BCL-2 proteins; protein–protein interactions
    DOI:  https://doi.org/10.1042/BST20220323
  15. Invest Ophthalmol Vis Sci. 2022 May 02. 63(5): 5
    Photoreceptor Manifestations of Primary Mitochondrial Optic Nerve Disorders.
    Yin-Hsi Chang, Eugene Yu-Chuan Kang, Pei-Kang Liu, Sarah R Levi, Hung-Hsuan Wang, Yun-Ju Tseng, Go Hun Seo, Hane Lee, Lung-Kun Yeh, Kuan-Jen Chen, Wei-Chi Wu, Chi-Chun Lai, Laura Liu, Nan-Kai Wang.
       Purpose: To compare the manifestations of photoreceptors (PRs) in three hereditary optic neuropathies affected by primary mitochondrial dysfunction and discuss whether the retinal ganglion cells (RGCs) or the PRs are preferentially affected.
    Methods: A retrospective analysis of patients with genetically confirmed diagnoses of optic neuropathies associated with mitochondrial dysfunction was performed. This cohort included Leber's hereditary optic neuropathy (LHON), autosomal dominant optic atrophy type 1 (OPA1), and optic atrophy type 13 (OPA13). Patient chart evaluations included clinical characteristics, best-corrected visual acuity (BCVA), fundus photography, spectral-domain optical coherence tomography (SD-OCT), electroretinogram (ERG), and visual evoked potential data.
    Results: This analysis included seven patients with LHON, six with OPA1, and one with OPA13 from a tertiary medical center. Thirteen of the 14 individuals were male. The average BCVA at diagnosis was 20/285 and 20/500 in the right and left eyes, respectively. Five of the seven patients with LHON, and three of the six patients with OPA1 also showed a mild amplitude reduction or delayed latency on light-adapted ERG and 30-Hz flicker responses; however, SD-OCT imaging did not show correlated PR abnormalities. Notably, a 7-year follow-up of a patient with OPA13 revealed degeneration of RGCs prior to the degeneration of PRs. Follow-up data also demonstrated continuous loss of cone outer segment tips on SD-OCT imaging.
    Conclusions: RGCs are, in general, affected by mitochondrial dysfunction, whereas variable PR dysfunction exists in patients with LHON and OPA1, especially with respect to the cone responses. Involvement of PRs is particularly evident in OPA13 after RGC degenerations.
    DOI:  https://doi.org/10.1167/iovs.63.5.5
  16. Nucleic Acids Res. 2022 May 07. pii: gkac306. [Epub ahead of print]
    The mitoXplorer 2.0 update: integrating and interpreting mitochondrial expression dynamics within a cellular context.
    Fabio Marchiano, Margaux Haering, Bianca Hermine Habermann.
      Mitochondria are subcellular organelles present in almost all eukaryotic cells, which play a central role in cellular metabolism. Different tissues, health and age conditions are characterized by a difference in mitochondrial structure and composition. The visual data mining platform mitoXplorer 1.0 was developed to explore the expression dynamics of genes associated with mitochondrial functions that could help explain these differences. It, however, lacked functions aimed at integrating mitochondria in the cellular context and thus identifying regulators that help mitochondria adapt to cellular needs. To fill this gap, we upgraded the mitoXplorer platform to version 2.0 (mitoXplorer 2.0). In this upgrade, we implemented two novel integrative functions, network analysis and transcription factor enrichment, to specifically help identify signalling or transcriptional regulators of mitochondrial processes. In addition, we implemented several other novel functions to allow the platform to go beyond simple data visualization, such as an enrichment function for mitochondrial processes, a function to explore time-series data, the possibility to compare datasets across species and an IDconverter to help facilitate data upload. We demonstrate the usefulness of these functions in three specific use cases. mitoXplorer 2.0 is freely available without login at http://mitoxplorer2.ibdm.univ-mrs.fr.
    DOI:  https://doi.org/10.1093/nar/gkac306
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