bims-mecmid 2022-02-20 papers

bims-mecmid

Biomed News

on Membrane communication in mitochondrial dynamics

Issue of 2022–02–20
fourteen papers selected by
Mauricio Cardenas Rodriguez, University of Padova

Mitochondrial fusion regulates proliferation and differentiation in the type II neuroblast lineage in Drosophila.
Targeting Mitochondrial COX-2 Enhances Chemosensitivity via Drp1-Dependent Remodeling of Mitochondrial Dynamics in Hepatocellular Carcinoma.
Oestrogenic Regulation of Mitochondrial Dynamics.
Protective effects of silibinin against ethanol- or acetaldehyde-caused damage in liver cell lines involve the repression of mitochondrial fission.
The strange case of Drp1 in autophagy: Jekyll and Hyde?
Mitochondrial Dynamics and Mitochondria-Lysosome Contacts in Neurogenetic Diseases.
The Mitochondrial PHB2/OMA1/DELE1 Pathway Cooperates with Endoplasmic Reticulum Stress to Facilitate the Response to Chemotherapeutics in Ovarian Cancer.
The essential cysteines in the CIPC motif of the thioredoxin-like Trypanosoma brucei MICOS subunit TbMic20 do not form an intramolecular disulfide bridge in vivo.
Biphasic effect of sulforaphane on angiogenesis in hypoxia via modulation of both Nrf2 and mitochondrial dynamics.
Mitochondrial fission links ECM mechanotransduction to metabolic redox homeostasis and metastatic chemotherapy resistance.
Uncoupling Proteins and Regulated Proton Leak in Mitochondria.
CHCHD2 and CHCHD10 regulate mitochondrial dynamics and integrated stress response.
Metabolic control of adult neural stem cell self-renewal by the mitochondrial protease YME1L.
BMAL1 regulates mitochondrial homeostasis in renal ischaemia-reperfusion injury by mediating the SIRT1/PGC-1α axis.

PLoS Genet. 2022 Feb 14. 18(2): e1010055

Mitochondrial fusion regulates proliferation and differentiation in the type II neuroblast lineage in Drosophila.

Dnyanesh Dubal, Prachiti Moghe, Rahul Kumar Verma, Bhavin Uttekar, Richa Rikhy.

Optimal mitochondrial function determined by mitochondrial dynamics, morphology and activity is coupled to stem cell differentiation and organism development. However, the mechanisms of interaction of signaling pathways with mitochondrial morphology and activity are not completely understood. We assessed the role of mitochondrial fusion and fission in the differentiation of neural stem cells called neuroblasts (NB) in the Drosophila brain. Depleting mitochondrial inner membrane fusion protein Opa1 and mitochondrial outer membrane protein Marf in the Drosophila type II NB lineage led to mitochondrial fragmentation and loss of activity. Opa1 and Marf depletion did not affect the numbers of type II NBs but led to a decrease in differentiated progeny. Opa1 depletion decreased the mature intermediate precursor cells (INPs), ganglion mother cells (GMCs) and neurons by the decreased proliferation of the type II NBs and mature INPs. Marf depletion led to a decrease in neurons by a depletion of proliferation of GMCs. On the contrary, loss of mitochondrial fission protein Drp1 led to mitochondrial clustering but did not show defects in differentiation. Depletion of Drp1 along with Opa1 or Marf also led to mitochondrial clustering and suppressed the loss of mitochondrial activity and defects in proliferation and differentiation in the type II NB lineage. Opa1 depletion led to decreased Notch signaling in the type II NB lineage. Further, Notch signaling depletion via the canonical pathway showed mitochondrial fragmentation and loss of differentiation similar to Opa1 depletion. An increase in Notch signaling showed mitochondrial clustering similar to Drp1 mutants. Further, Drp1 mutant overexpression combined with Notch depletion showed mitochondrial fusion and drove differentiation in the lineage, suggesting that fused mitochondria can influence differentiation in the type II NB lineage. Our results implicate crosstalk between proliferation, Notch signaling, mitochondrial activity and fusion as an essential step in differentiation in the type II NB lineage.

DOI: https://doi.org/10.1371/journal.pgen.1010055
Cancers (Basel). 2022 Feb 06. pii: 821. [Epub ahead of print]14(3):

Targeting Mitochondrial COX-2 Enhances Chemosensitivity via Drp1-Dependent Remodeling of Mitochondrial Dynamics in Hepatocellular Carcinoma.

Lin Che, Jia-Shen Wu, Ze-Bang Du, Yu-Qiao He, Lei Yang, Jin-Xian Lin, Zhao Lei, Xiao-Xuan Chen, Dong-Bei Guo, Wen-Gang Li, Yu-Chun Lin, Zhong-Ning Lin.

  Mitochondria are highly dynamic organelles and undergo constant fission and fusion, which are both essential for the maintenance of cell physiological functions. Dysregulation of dynamin-related protein 1 (Drp1)-dependent mitochondrial dynamics is associated with tumorigenesis and the chemotherapeutic response in hepatocellular carcinoma (HCC). The enzyme cyclooxygenase-2 (COX-2) is overexpressed in most cancer types and correlates with a poor prognosis. However, the roles played by the translocation of mitochondrial COX-2 (mito-COX-2) and the interaction between mito-COX-2 and Drp1 in chemotherapeutic responses remain to be elucidated in the context of HCC. Bioinformatics analysis, paired HCC patient specimens, xenograft nude mice, immunofluorescence, transmission electron microscopy, molecular docking, CRISPR/Cas9 gene editing, proximity ligation assay, cytoplasmic and mitochondrial fractions, mitochondrial immunoprecipitation assay, and flow cytometry analysis were performed to evaluate the underlying mechanism of how mito-COX-2 and p-Drp1Ser616 interaction regulates the chemotherapeutic response via mitochondrial dynamics in vitro and in vivo. We found that COX-2 and Drp1 were frequently upregulated and confer a poor prognosis in HCC. We also found that the proportion of mito-COX-2 and p-Drp1Ser616 was increased in HCC cell lines. In vitro, we demonstrated that the enhanced mitochondrial translocation of COX-2 promotes its interaction with p-Drp1Ser616 via PTEN-induced putative kinase 1 (PINK1)-mediated Drp1 phosphorylation activation. This increase was associated with higher colony formation, cell proliferation, and mitochondrial fission. These findings were confirmed by knocking down COX-2 in HCC cells using CRISPR/Cas9 technology. Furthermore, inhibition of Drp1 using pharmacologic inhibitors (Mdivi-1) or RNA interference (siDNM1L) decreased mito-COX-2/p-Drp1Ser616 interaction-mediated mitochondrial fission, and increased apoptosis in HCC cells treated with platinum drugs. Moreover, inhibiting mito-COX-2 acetylation with the natural phytochemical resveratrol resulted in reducing cell proliferation and mitochondrial fission, occurring through upregulation of mitochondrial deacetylase sirtuin 3 (SIRT3), which, in turn, increased the chemosensitivity of HCC to platinum drugs in vitro and in vivo. Our results suggest that targeting interventions to PINK1-mediated mito-COX-2/p-Drp1Ser616-dependent mitochondrial dynamics increases the chemosensitivity of HCC and might help us to understand how to use the SIRT3-modulated mito-COX-2/p-Drp1Ser616 signaling axis to develop an effective clinical intervention in hepatocarcinogenesis.

Keywords:  apoptosis; dynamin-related protein 1; hepatocellular carcinoma; mitochondrial cyclooxygenase-2; mitochondrial dynamics; sirtuin 3

DOI:  https://doi.org/10.3390/cancers14030821
Int J Mol Sci. 2022 Jan 20. pii: 1118. [Epub ahead of print]23(3):

Oestrogenic Regulation of Mitochondrial Dynamics.

Siavash Beikoghli Kalkhoran, Georgios Kararigas.

  Biological sex influences disease development and progression. The steroid hormone 17β-oestradiol (E2), along with its receptors, is expected to play a major role in the manifestation of sex differences. E2 exerts pleiotropic effects in a system-specific manner. Mitochondria are one of the central targets of E2, and their biogenesis and respiration are known to be modulated by E2. More recently, it has become apparent that E2 also regulates mitochondrial fusion-fission dynamics, thereby affecting cellular metabolism. The aim of this article is to discuss the regulatory pathways by which E2 orchestrates the activity of several components of mitochondrial dynamics in the cardiovascular and nervous systems in health and disease. We conclude that E2 regulates mitochondrial dynamics to maintain the mitochondrial network promoting mitochondrial fusion and attenuating mitochondrial fission in both the cardiovascular and nervous systems.

Keywords:  17β-oestradiol; biological sex; cardiovascular; heart–brain axis; neuronal

DOI:  https://doi.org/10.3390/ijms23031118
Toxicol In Vitro. 2022 Feb 11. pii: S0887-2333(22)00027-3. [Epub ahead of print] 105330

Protective effects of silibinin against ethanol- or acetaldehyde-caused damage in liver cell lines involve the repression of mitochondrial fission.

Xiao-Yu Song, Peng-Cheng Liu, Wei-Wei Liu, Toshihiko Hayashi, Kazunori Mizuno, Shunji Hattori, Hitomi Fujisaki, Takashi Ikejima.

  Silibinin is a natural polyphenolic flavonoid, isolated from the seeds of the milk thistle of Silybum marianum (L.) Gaertn. Silibinin has been widely used clinically as a traditional medicine for liver diseases. This study investigated the protective role of silibinin in ethanol- or acetaldehyde-induced apoptosis in human carcinomatous liver HepG2 cells and immortalized liver HL7702 cells, focusing on elucidation of the underlying mechanism in vitro. The toxicity of ethanol or acetaldehyde was evaluated by MTT assay. Apoptosis-related proteins, mitochondrial fission-associated proteins and mitochondrial fusion-associated proteins were analyzed by western blotting and immunofluorescence microscopy. Present experimental results demonstrated that silibinin improved cell viability, reduced the enzyme activities of AST/ALT and ALDH/ADH, inhibited apoptosis and recovered mitochondrial function in ethanol- or acetaldehyde-treated HepG2 or HL7702 cells. Silibinin reduced the expression of mitochondrial fission-associated proteins, dynamin-related protein 1 (DRP1), but increased mitochondrial fusion-associated proteins, optic atrophy 1 (OPA1) and mitofusin 1 (MFN1). Accordingly, inhibition of DRP1 activity with its pharmacological inhibitor or siDRP1 efficiently attenuated ethanol- or acetaldehyde-induced apoptosis, whereas activation of DRP1 by using staurosporine (STS) further increased apoptosis in ethanol- or acetaldehyde-treated HepG2 or HL7702 cells. The results show that silibinin protects cells against ethanol- or acetaldehyde-induced mitochondrial fission that results in apoptosis.

Keywords:  Acetaldehyde; Apoptosis; Ethanol; Mitochondrial fission; Silibinin

DOI:  https://doi.org/10.1016/j.tiv.2022.105330
Bioessays. 2022 Feb 15. e2100271

The strange case of Drp1 in autophagy: Jekyll and Hyde?

Yanfang Chen, Emmanuel Culetto, Renaud Legouis.

  There is a debate regarding the function of Drp1, a GTPase involved in mitochondrial fission, during the elimination of mitochondria by autophagy. A number of experiments indicate that Drp1 is needed to eliminate mitochondria during mitophagy, either by reducing the mitochondrial size or by providing a noncanonical mitophagy function. Yet, other convincing experimental results support the conclusion that Drp1 is not necessary. Here, we review the possible functions for Drp1 in mitophagy and autophagy, depending on tissues, organisms and stresses, and discuss these apparent discrepancies. In this regard, it appears that the reduction of mitochondria size is often required for mitophagy but not always in a Drp1-dependent manner. Finally, we speculate on Drp1-independent mitochondrial fission mechanism that may take place during mitophagy and on noncanonical roles, which Drp1 may play such as modulating organelle contact sites dynamic during the autophagosome formation.

Keywords:  Dnm1; Drp1; MERCs; autophagosome; fission; mitochondria; mitophagy

DOI:  https://doi.org/10.1002/bies.202100271
Front Neurosci. 2022 ;16 784880

Mitochondrial Dynamics and Mitochondria-Lysosome Contacts in Neurogenetic Diseases.

Jordi Pijuan, Lara Cantarero, Daniel Natera-de Benito, Arola Altimir, Anna Altisent-Huguet, Yaiza Díaz-Osorio, Laura Carrera-García, Jessica Expósito-Escudero, Carlos Ortez, Andrés Nascimento, Janet Hoenicka, Francesc Palau.

  Mitochondrial network is constantly in a dynamic and regulated balance of fusion and fission processes, which is known as mitochondrial dynamics. Mitochondria make physical contacts with almost every other membrane in the cell thus impacting cellular functions. Mutations in mitochondrial dynamics genes are known to cause neurogenetic diseases. To better understand the consequences on the cellular phenotype and pathophysiology of neurogenetic diseases associated with defective mitochondrial dynamics, we have compared the fibroblasts phenotypes of (i) patients carrying pathogenic variants in genes involved in mitochondrial dynamics such as DRP1 (also known as DNM1L), GDAP1, OPA1, and MFN2, and (ii) patients carrying mutated genes that their dysfunction affects mitochondria or induces a mitochondrial phenotype, but that are not directly involved in mitochondrial dynamic network, such as FXN (encoding frataxin, located in the mitochondrial matrix), MED13 (hyperfission phenotype), and CHKB (enlarged mitochondria phenotype). We identified mitochondrial network alterations in all patients' fibroblasts except for CHKB Q198*/Q198*. Functionally, all fibroblasts showed mitochondrial oxidative stress, without membrane potential abnormalities. The lysosomal area and distribution were abnormal in GDAP1 W67L/W67L, DRP1 K75E/+, OPA1 F570L/+, and FXN R165C/GAA fibroblasts. These lysosomal alterations correlated with mitochondria-lysosome membrane contact sites (MCSs) defects in GDAP1 W67L/W67L exclusively. The study of mitochondrial contacts in all samples further revealed a significant decrease in MFN2 R104W/+ fibroblasts. GDAP1 and MFN2 are outer mitochondrial membrane (OMM) proteins and both are related to Charcot-Marie Tooth neuropathy. Here we identified their constitutive interaction as well as MFN2 interaction with LAMP-1. Therefore MFN2 is a new mitochondria-lysosome MCSs protein. Interestingly, GDAP1 W67L/W67L and MFN2 R104W/+ fibroblasts carry pathogenic changes that occur in their catalytic domains thus suggesting a functional role of GDAP1 and MFN2 in mitochondria-lysosome MCSs. Finally, we observed starvation-induced autophagy alterations in DRP1 K75E/+, GDAP1 W67L/W67L, OPA1 F570L/+, MFN2 R104W/+, and CHKB Q198*/Q198* fibroblasts. These genes are related to mitochondrial membrane structure or lipid composition, which would associate the OMM with starvation-induced autophagy. In conclusion, the study of mitochondrial dynamics and mitochondria-lysosome axis in a group of patients with different neurogenetic diseases has deciphered common and unique cellular phenotypes of degrading and non-degrading pathways that shed light on pathophysiological events, new biomarkers and pharmacological targets for these disorders.

Keywords:  lysosome; membrane contact sites (MCSs); mitochondria; mitochondrial dynamics; neurogenetic diseases

DOI:  https://doi.org/10.3389/fnins.2022.784880
Int J Mol Sci. 2022 Jan 25. pii: 1320. [Epub ahead of print]23(3):

The Mitochondrial PHB2/OMA1/DELE1 Pathway Cooperates with Endoplasmic Reticulum Stress to Facilitate the Response to Chemotherapeutics in Ovarian Cancer.

Meiyu Cheng, Huimei Yu, Qinghuan Kong, Bingrong Wang, Luyan Shen, Delu Dong, Liankun Sun.

  Interactions between the mitochondrial inner and outer membranes and between mitochondria and other organelles closely correlates with the sensitivity of ovarian cancer to cisplatin and other chemotherapeutic drugs. However, the underlying mechanism remains unclear. Recently, the mitochondrial protease OMA1, which regulates internal and external signals in mitochondria by cleaving mitochondrial proteins, was shown to be related to tumor progression. Therefore, we evaluated the effect of OMA1 on the response to chemotherapeutics in ovarian cancer cells and the mouse subcutaneous tumor model. We found that OMA1 activation increased ovarian cancer sensitivity to cisplatin in vivo and in vitro. Mechanistically, in ovarian cancer, OMA1 cleaved optic atrophy 1 (OPA1), leading to mitochondrial inner membrane cristae remodeling. Simultaneously, OMA1 induced DELE1 cleavage and its cytoplasmic interaction with EIF2AK1. We also demonstrated that EIF2AK1 cooperated with the ER stress sensor EIF2AK3 to amplify the EIF2S1/ATF4 signal, resulting in the rupture of the mitochondrial outer membrane. Knockdown of OMA1 attenuated these activities and reversed apoptosis. Additionally, we found that OMA1 protease activity was regulated by the prohibitin 2 (PHB2)/stomatin-like protein 2 (STOML2) complex. Collectively, OMA1 coordinates the mitochondrial inner and outer membranes to induce ovarian cancer cell death. Thus, activating OMA1 may be a novel treatment strategy for ovarian cancer.

Keywords:  DELE1; OMA1; endoplasmic reticulum stress; mitochondrial membranes; ovarian cancer

DOI:  https://doi.org/10.3390/ijms23031320
Mol Biochem Parasitol. 2022 Feb 11. pii: S0166-6851(22)00017-2. [Epub ahead of print]248 111463

The essential cysteines in the CIPC motif of the thioredoxin-like Trypanosoma brucei MICOS subunit TbMic20 do not form an intramolecular disulfide bridge in vivo.

Iosif Kaurov, Jiří Heller, Sebastian Deisenhammer, David Potěšil, Zbyněk Zdráhal, Hassan Hashimi.

  The mitochondrial protein import machinery of trypanosomatids is highly divergent from that of the well-studied models such as baker's yeast. A notable example is that the central catalyst of the mitochondrial intermembrane space import and assembly pathway (MIA), named Mia40, is missing in trypanosomatids. Mia40 works in a two-step process. First it recognizes by direct binding reduced MIA substrate proteins and then catalyzes their oxidative folding to produce intramolecular disulfide bridges. It was recently proposed that a thioredoxin-like subunit of the trypanosomal mitochondrial contact site and cristae organizing system (MICOS) called TbMic20 may be the Mia40 replacement. Our study performed on procyclic stage of the parasite revealed that each of the two cysteines in TbMic20's active site is essential for the stability of MIA substrate proteins although they do not form a disulfide bridge in vivo. The two cysteines of Mia40's active site form an intramolecular disulfide bridge at steady state, which is a prerequisite for its oxidative folding of MIA substrates. Thus, we conclude that TbMic20 is unlikely to represent a bona fide Mia40 replacement and plays a still unresolved role in the stability and/or import of MIA substrates in trypanosomatids. Despite this, the effect of TbMic20 depletion and mutation indicates that the trypanosomal MICOS complex still plays a vital role in the maturation and/or stability of proteins imported by the MIA pathway.

Keywords:  Intermembrane space; MICOS; Mitochondrion; Oxidative folding; Protein import; Trypanosoma

DOI:  https://doi.org/10.1016/j.molbiopara.2022.111463
Food Funct. 2022 Feb 18.

Biphasic effect of sulforaphane on angiogenesis in hypoxia via modulation of both Nrf2 and mitochondrial dynamics.

Yaqian Wang, Fangfang Chen, Yuan Zhang, Xiangyu Zheng, Shiyan Liu, Meijuan Tang, Ziling Wang, Pan Wang, Yongping Bao, Dan Li.

Sulforaphane (SFN) is an isothiocyanate (ITC) derived from a glucosinolate, glucoraphinin found in cruciferous vegetables. There are few studies that focus on the role of SFN in angiogenesis under hypoxic conditions. The effect of SFN on angiogenesis and the underlying mechanisms including the roles of Nrf2 and mitochondrial dynamics were investigated using cultured human umbilical vein endothelial cells (HUVECs) in hypoxia. SFN at low doses (1.25-5 μM) increased hypoxia-induced HUVEC migration and tube formation, and alleviated hypoxia-induced retarded proliferation, but high doses (≥10 μM) exhibited an opposite effect. Under hypoxia, the expression of Nrf2 and heme oxygenase-1 was up-regulated by SFN treatment. Nrf2 knockdown abrogated SFN (2.5 μM)-induced tube formation and further potentiated the inhibitory effect of SFN (10 μM) on angiogenesis. Meanwhile, the mitochondrial function, morphology and expression of dynamic-related proteins suggested that low-dose SFN protected against hypoxia-induced mitochondrial injury and alleviated hypoxia-induced fission Nrf2-dependently without affecting the expression of key effector proteins (Drp1, Fis1, Mfn1/2 and Opa1), while high concentrations (≥10 μM SFN) aggravated hypoxia-induced mitochondrial injury, fission and Drp1 expression, and inhibited Mfn1/2 expression. These findings suggest that SFN biphasically affected the angiogenic capacity of hypoxia challenged HUVECs potentially via mechanisms involving an integrated modulation of Nrf2 and mitochondrial dynamics.

DOI: https://doi.org/10.1039/d1fo04112f
Nat Cell Biol. 2022 Feb;24(2): 168-180

Mitochondrial fission links ECM mechanotransduction to metabolic redox homeostasis and metastatic chemotherapy resistance.

Patrizia Romani, Nunzia Nirchio, Mattia Arboit, Vito Barbieri, Anna Tosi, Federica Michielin, Soichi Shibuya, Thomas Benoist, Danchen Wu, Charles Colin Thomas Hindmarch, Monica Giomo, Anna Urciuolo, Flavia Giamogante, Antonella Roveri, Probir Chakravarty, Marco Montagner, Tito Calì, Nicola Elvassore, Stephen L Archer, Paolo De Coppi, Antonio Rosato, Graziano Martello, Sirio Dupont.

Metastatic breast cancer cells disseminate to organs with a soft microenvironment. Whether and how the mechanical properties of the local tissue influence their response to treatment remains unclear. Here we found that a soft extracellular matrix empowers redox homeostasis. Cells cultured on a soft extracellular matrix display increased peri-mitochondrial F-actin, promoted by Spire1C and Arp2/3 nucleation factors, and increased DRP1- and MIEF1/2-dependent mitochondrial fission. Changes in mitochondrial dynamics lead to increased production of mitochondrial reactive oxygen species and activate the NRF2 antioxidant transcriptional response, including increased cystine uptake and glutathione metabolism. This retrograde response endows cells with resistance to oxidative stress and reactive oxygen species-dependent chemotherapy drugs. This is relevant in a mouse model of metastatic breast cancer cells dormant in the lung soft tissue, where inhibition of DRP1 and NRF2 restored cisplatin sensitivity and prevented disseminated cancer-cell awakening. We propose that targeting this mitochondrial dynamics- and redox-based mechanotransduction pathway could open avenues to prevent metastatic relapse.

DOI: https://doi.org/10.1038/s41556-022-00843-w
Int J Mol Sci. 2022 Jan 28. pii: 1528. [Epub ahead of print]23(3):

Uncoupling Proteins and Regulated Proton Leak in Mitochondria.

Afshan Ardalan, Matthew D Smith, Masoud Jelokhani-Niaraki.

  Higher concentration of protons in the mitochondrial intermembrane space compared to the matrix results in an electrochemical potential causing the back flux of protons to the matrix. This proton transport can take place through ATP synthase complex (leading to formation of ATP) or can occur via proton transporters of the mitochondrial carrier superfamily and/or membrane lipids. Some mitochondrial proton transporters, such as uncoupling proteins (UCPs), transport protons as their general regulating function; while others are symporters or antiporters, which use the proton gradient as a driving force to co-transport other substrates across the mitochondrial inner membrane (such as phosphate carrier, a symporter; or aspartate/glutamate transporter, an antiporter). Passage (or leakage) of protons across the inner membrane to matrix from any route other than ATP synthase negatively impacts ATP synthesis. The focus of this review is on regulated proton transport by UCPs. Recent findings on the structure and function of UCPs, and the related research methodologies, are also critically reviewed. Due to structural similarity of members of the mitochondrial carrier superfamily, several of the known structural features are potentially expandable to all members. Overall, this report provides a brief, yet comprehensive, overview of the current knowledge in the field.

Keywords:  ADP/ATP carrier; ATP synthesis; alternating access mechanism; biphasic proton transport model; membrane protein oligomerization; membrane protein structure and function; mitochondrial carriers; reactive oxygen species control; regulation and mechanism of proton transport; uncoupling proteins

DOI:  https://doi.org/10.3390/ijms23031528
Cell Death Dis. 2022 02 16. 13(2): 156

CHCHD2 and CHCHD10 regulate mitochondrial dynamics and integrated stress response.

Yu Ruan, Jiaqiao Hu, Yaping Che, Yanyan Liu, Zhenhuan Luo, Jin Cheng, Qi Han, He He, Qinghua Zhou.

Mitochondrial dysfunction is becoming one of the main pathology factors involved in the etiology of neurological disorders. Recently, mutations of the coiled-coil-helix-coiled-coil-helix domain containing 2 (CHCHD2) and 10 (CHCHD10) which encode two homologous proteins that belong to the mitochondrial CHCH domain protein family, are linked to Parkinson's disease and amyotrophic lateral sclerosis (ALS)/frontotemporal dementia (FTD), respectively. However, the physiological and pathological roles of these twin proteins have not been well elaborated. Here, we show that, in physiological conditions, CHCHD2 and CHCHD10 interact with OMA1 and suppress its enzyme activity, which not only restrains the initiation of the mitochondrial integrated response stress (mtISR), but also suppresses the processing of OPA1 for mitochondrial fusion. Further, during mitochondria stress-induced by carbonyl cyanide m-chlorophenylhydrazone (CCCP) treatment, CHCHD2 and CHCHD10 translocate to the cytosol and interacte with eIF2a, which attenuates mtISR overactivation by suppressing eIF2a phosphorylation and its downstream response. As such, knockdown of CHCHD2 and CHCHD10 triggers mitochondrial ISR, and such cellular response is enhanced by CCCP treatment. Therefore, our findings demonstrate the first "mtISR suppressor" localized in mitochondria for regulating stress responses in mammalian cells, which has a profound pathological impact on the CHCH2/CHCH10-linked neurodegenerative disorder.

DOI: https://doi.org/10.1038/s41419-022-04602-5
Cell Rep. 2022 02 15. pii: S2211-1247(22)00091-2. [Epub ahead of print]38(7): 110370

Metabolic control of adult neural stem cell self-renewal by the mitochondrial protease YME1L.

Gulzar A Wani, Hans-Georg Sprenger, Kristiano Ndoci, Srikanth Chandragiri, Richard James Acton, Désirée Schatton, Sandra M V Kochan, Vignesh Sakthivelu, Milica Jevtic, Jens M Seeger, Stefan Müller, Patrick Giavalisco, Elena I Rugarli, Elisa Motori, Thomas Langer, Matteo Bergami.

  The transition between quiescence and activation in neural stem and progenitor cells (NSPCs) is coupled with reversible changes in energy metabolism with key implications for lifelong NSPC self-renewal and neurogenesis. How this metabolic plasticity is ensured between NSPC activity states is unclear. We find that a state-specific rewiring of the mitochondrial proteome by the i-AAA peptidase YME1L is required to preserve NSPC self-renewal. YME1L controls the abundance of numerous mitochondrial substrates in quiescent NSPCs, and its deletion activates a differentiation program characterized by broad metabolic changes causing the irreversible shift away from a fatty-acid-oxidation-dependent state. Conditional Yme1l deletion in adult NSPCs in vivo results in defective self-renewal and premature differentiation, ultimately leading to NSPC pool depletion. Our results disclose an important role for YME1L in coordinating the switch between metabolic states of NSPCs and suggest that NSPC fate is regulated by compartmentalized changes in protein network dynamics.

Keywords:  OMA1; YME1L; adult neurogenesis; metabolic rewiring; mitochondria; mitochondrial dynamics; mitochondrial proteome; neural stem cells; proliferation; self-renewal

DOI:  https://doi.org/10.1016/j.celrep.2022.110370
J Cell Mol Med. 2022 Feb 17.

BMAL1 regulates mitochondrial homeostasis in renal ischaemia-reperfusion injury by mediating the SIRT1/PGC-1α axis.

Peng Ye, Wei Li, Xin Huang, Sheng Zhao, Wu Chen, Yuqi Xia, Weimin Yu, Ting Rao, Jinzhuo Ning, Xiangjun Zhou, Yuan Ruan, Fan Cheng.

  The regulation of renal function by circadian gene BMAL1 has been recently recognized; however, the role and mechanism of BMAL1 in renal ischaemia-reperfusion injury (IRI) are still unknown. The purpose of this study was to clarify the pathophysiological role of BMAL1 in renal IRI. We measured the levels of BMAL1 and mitochondrial biogenesis-related proteins, including SIRT1, PGC-1α, NRF1 and TFAM, in rats with renal IRI. In rats, the level of BMAL1 decreased significantly, resulting in inhibition of SIRT1 expression and mitochondrial biogenesis. In addition, under hypoxia and reoxygenation (H/R) stimulation, BMAL1 knockdown decreased the level of SIRT1 and exacerbated the degree of mitochondrial damage and apoptosis. Overexpression of BMAL1 alleviated H/R-induced injury. Furthermore, application of the SIRT1 inhibitor EX527 not only reduced the activities of SIRT1 and PGC-1α but also further aggravated mitochondrial dysfunction and partially reversed the protective effect of BMAL1 overexpression. Moreover, whether in vivo or in vitro, the application of SIRT1 agonist resveratrol rescued the mitochondrial dysfunction caused by H/R or IRI by activating mitochondrial biogenesis. These results indicate that BMAL1 is a key circadian gene that mediates mitochondrial homeostasis in renal IRI through the SIRT1/PGC-1α axis, which provides a new direction for targeted therapy for renal IRI.

Keywords:  BMAL1; SIRT1/PGC-1α; mitochondrial biogenesis; renal IRI

DOI:  https://doi.org/10.1111/jcmm.17223