bims-mikwok 2023-07-16 papers

bims-mikwok

Biomed News

on Mitochondrial quality control

Issue of 2023‒07‒16
ten papers selected by
Gavin McStay, Liverpool John Moores University

Hypoxia-reprogramed megamitochondrion contacts and engulfs lysosome to mediate mitochondrial self-digestion.
Deciphering the mitophagy receptor network identifies a crucial role for OPTN (optineurin) in acute myeloid leukemia.
Tethering ATG16L1 or LC3 induces targeted autophagic degradation of protein aggregates and mitochondria.
The role of mitochondria and mitophagy in cell senescence.
Prostacyclin mimetics inhibit DRP1-mediated pro-proliferative mitochondrial fragmentation in pulmonary arterial hypertension.
High-Intensity Interval Training Attenuates Impairment in Regulatory Protein Machinery of Mitochondrial Quality Control in Skeletal Muscle of Diet-Induced Obese Mice.
Mitochondrial quality control and its emerging role in the pathogenesis of diabetic kidney disease.
Notch signaling regulates a metabolic switch through inhibiting PGC-1α and mitochondrial biogenesis in dedifferentiated liposarcoma.
Lysosomal mitochondrial interaction promotes tumor growth in squamous cell carcinoma of the head and neck.
Defects in Mitochondrial Biogenesis Drive Mitochondrial Alterations in PINK1-deficient Human Dopamine Neurons.

Nat Commun. 2023 07 11. 14(1): 4105

Hypoxia-reprogramed megamitochondrion contacts and engulfs lysosome to mediate mitochondrial self-digestion.

Tianshu Hao, Jianglong Yu, Zhida Wu, Jie Jiang, Longlong Gong, Bingjun Wang, Hanze Guo, Huabin Zhao, Bin Lu, Simone Engelender, He He, Zhiyin Song.

Mitochondria are the key organelles for sensing oxygen, which is consumed by oxidative phosphorylation to generate ATP. Lysosomes contain hydrolytic enzymes that degrade misfolded proteins and damaged organelles to maintain cellular homeostasis. Mitochondria physically and functionally interact with lysosomes to regulate cellular metabolism. However, the mode and biological functions of mitochondria-lysosome communication remain largely unknown. Here, we show that hypoxia remodels normal tubular mitochondria into megamitochondria by inducing broad inter-mitochondria contacts and subsequent fusion. Importantly, under hypoxia, mitochondria-lysosome contacts are promoted, and certain lysosomes are engulfed by megamitochondria, in a process we term megamitochondria engulfing lysosome (MMEL). Both megamitochondria and mature lysosomes are required for MMEL. Moreover, the STX17-SNAP29-VAMP7 complex contributes to mitochondria-lysosome contacts and MMEL under hypoxia. Intriguingly, MMEL mediates a mode of mitochondrial degradation, which we termed mitochondrial self-digestion (MSD). Moreover, MSD increases mitochondrial ROS production. Our results reveal a mode of crosstalk between mitochondria and lysosomes and uncover an additional pathway for mitochondrial degradation.

DOI: https://doi.org/10.1038/s41467-023-39811-9
Autophagy. 2023 Jul 13. 1-15

Deciphering the mitophagy receptor network identifies a crucial role for OPTN (optineurin) in acute myeloid leukemia.

Laura M Meyer, Sebastian E Koschade, Jonas B Vischedyk, Marlyn Thoelken, Andrea Gubas, Martin Wegner, Marion Basoglu, Stefan Knapp, Manuel Kaulich, Stefan Eimer, Shabnam Shaid, Christian H Brandts.

  The selective autophagic degradation of mitochondria via mitophagy is essential for preserving mitochondrial homeostasis and, thereby, disease maintenance and progression in acute myeloid leukemia (AML). Mitophagy is orchestrated by a variety of mitophagy receptors whose interplay is not well understood. Here, we established a pairwise multiplexed CRISPR screen targeting mitophagy receptors to elucidate redundancies and gain a deeper understanding of the functional interactome governing mitophagy in AML. We identified OPTN (optineurin) as sole non-redundant mitophagy receptor and characterized its unique role in AML. Knockdown and overexpression experiments demonstrated that OPTN expression is rate-limiting for AML cell proliferation. In a MN1-driven murine transplantation model, loss of OPTN prolonged overall median survival by 7 days (+21%). Mechanistically, we found broadly impaired mitochondrial respiration and function with increased mitochondrial ROS, that most likely caused the proliferation defect. Our results decipher the intertwined network of mitophagy receptors in AML for both ubiquitin-dependent and receptor-mediated mitophagy, identify OPTN as a non-redundant tool to study mitophagy in the context of leukemia and suggest OPTN inhibition as an attractive therapeutic strategy.Abbreviations: AML: acute myeloid leukemia; CRISPR: Clustered Regularly Interspaced Short Palindromic Repeats; CTRL: control; DFP: deferiprone; GI: genetic interaction; KD: knockdown; KO: knockout; ldMBM, lineage-depleted murine bone marrow; LFC: log2 fold change; LIR: LC3-interacting region; LSC: leukemic stem cell; MAGeCK: Model-based Analysis of Genome-wide CRISPR-Cas9 Knockout; MDIVI-1: mitochondrial division inhibitor 1; MOI: multiplicity of infection; MOM: mitochondrial outer membrane; NAC: N-acetyl-L-cysteine; OA: oligomycin-antimycin A; OCR: oxygen consumption rate; OE: overexpression; OPTN: optineurin; PINK1: PTEN induced putative kinase 1; ROS: reactive oxygen species; SEM: standard error of the mean; TCGA: The Cancer Genome Atlas; TEM: transmission electron microscopy; UBD: ubiquitin-binding domain; WT: wild type.

Keywords:  AML; MN1-driven mouse model; Mitochondrial ROS; Multiplex CRISPR screen; genetic interactions; leukemia

DOI:  https://doi.org/10.1080/15548627.2023.2230839
Autophagy. 2023 Jul 13. 1-17

Tethering ATG16L1 or LC3 induces targeted autophagic degradation of protein aggregates and mitochondria.

Ligang Mei, Xiaorong Chen, Fujing Wei, Xue Huang, Lu Liu, Jia Yao, Jing Chen, Xunguang Luo, Zhuolin Wang, Aimin Yang.

  Proteolysis-targeting chimeras (PROTACs) based on the ubiquitin-proteasome system have made great progress in the field of drug discovery. There is mounting evidence that the accumulation of aggregation-prone proteins or malfunctioning organelles is associated with the occurrence of various age-related neurodegenerative disorders and cancers. However, PROTACs are inefficient for the degradation of such large targets due to the narrow entrance channel of the proteasome. Macroautophagy (hereafter referred to as autophagy) is known as a self-degradative process involved in the degradation of bulk cytoplasmic components or specific cargoes that are sequestered into autophagosomes. In the present study, we report the development of a generalizable strategy for the targeted degradation of large targets. Our results suggested that tethering large target models to phagophore-associated ATG16L1 or LC3 induced targeted autophagic degradation of the large target models. Furthermore, we successfully applied this autophagy-targeting degradation strategy to the targeted degradation of HTT65Q aggregates and mitochondria. Specifically, chimeras consisting of polyQ-binding peptide 1 (QBP) and ATG16L1-binding peptide (ABP) or LC3-interacting region (LIR) induced targeted autophagic degradation of pathogenic HTT65Q aggregates; and the chimeras consisting of mitochondria-targeting sequence (MTS) and ABP or LIR promoted targeted autophagic degradation of dysfunctional mitochondria, hence ameliorating mitochondrial dysfunction in a Parkinson disease cell model and protecting cells from apoptosis induced by the mitochondrial stress agent FCCP. Therefore, this study provides a new strategy for the selective proteolysis of large targets and enrich the toolkit for autophagy-targeting degradation.Abbreviations: ABP: ATG16L1-binding peptide; ATG16L1: autophagy related 16 like 1; ATTEC: autophagy-tethering compound; AUTAC: autophagy-targeting chimera; AUTOTAC: autophagy-targeting chimera; Baf A1: bafilomycin A1; BCL2: BCL2 apoptosis regulator; CALCOCO2/NDP52: calcium binding and coiled-coil domain 2; CASP3: caspase 3; CPP: cell-penetrating peptide; CQ: chloroquine phosphate; DAPI: 4',6-diamidino-2-phenylindole; DCM: dichloromethane; DMF: N,N-dimethylformamide; DMSO: dimethyl sulfoxide; EBSS: Earle's balanced salt solution; FCCP: carbonyl cyanide 4-(trifluoromethoxy)phenylhydrazone; FITC: fluorescein-5-isothiocyanate; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GFP: green fluorescent protein; HEK293: human embryonic kidney 293; HEK293T: human embryonic kidney 293T; HPLC: high-performance liquid chromatography; HRP: horseradish peroxidase; HTT: huntingtin; LIR: LC3-interacting region; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MFF: mitochondrial fission factor; MTS: mitochondria-targeting sequence; NBR1: NBR1 autophagy cargo receptor; NLRX1: NLR family member X1; OPTN: optineurin; P2A: self-cleaving 2A peptide; PB1: Phox and Bem1p; PBS: phosphate-buffered saline; PE: phosphatidylethanolamine; PINK1: PTEN induced kinase 1; PRKN: parkin RBR E3 ubiquitin protein ligase; PROTACs: proteolysis-targeting chimeras; QBP: polyQ-binding peptide 1; SBP: streptavidin-binding peptide; SDS-PAGE: sodium dodecyl sulfate-polyacrylamide gel electrophoresis; SPATA33: spermatogenesis associated 33; TIMM23: translocase of inner mitochondrial membrane 23; TMEM59: transmembrane protein 59; TOMM20: translocase of outer mitochondrial membrane 20; UBA: ubiquitin-associated; WT: wild type.

Keywords:  ATG16L1; HTT65Q aggregates; LC3; autophagy-targeting degradation; mitochondria; proteolysis-targeting chimeras

DOI:  https://doi.org/10.1080/15548627.2023.2234797
Adv Protein Chem Struct Biol. 2023 ;pii: S1876-1623(23)00043-3. [Epub ahead of print]136 93-115

The role of mitochondria and mitophagy in cell senescence.

Tayyab Ali, Fatma Hussain, Haroon Ur Rashid Kayani, Muhammad Naeem, Fozia Anjum.

  Mitochondrial malfunction and cell senescence have been defined as the hallmarks of aging. Cell senescence leads to the loss of health allied with aging. While deciphering the complex association between mitochondria and cellular senescence, it is observed that senescence has a two-faced nature being beneficial and hazardous. This duality of cellular senescence is associated with circumstantial aspects. During the process of cellular senescence, dysfunctional mitochondria are accumulated, the efficiency of the oxidative phosphorylation process declines along with the enhanced synthesis of reactive oxygen species. It is suggested that reduction in the negative consequences of senescence throughout old age might be accomplished by targeting the mitochondria as all roads lead towards mitochondria. It is unclear how perturbation of mitophagy in senescence results in the accumulation of mitochondria, impairment of mitochondrial biogenesis and onset of diseases. Understanding this complex interplay will bring about a long yet healthy lifespan. But definitely casual and specific players contribute in the initiation and conservation of the cell senescence. Variations in metabolism, quality control and dynamics of mitochondria are observed during cell aging process. Several On-target and Off-target mechanisms can also cause side effects in cellular senescence. Translational research of these mechanisms may lead to effective clinical interventions. This chapter reviews the role of mitochondria, homeostatic mechanisms and mitophagy as drivers and effectors of cell senescence along with multiple signalling pathways that lead to the initiation, maintenance, induction and suppression of cellular aging process during health and disease.

Keywords:  Autophagy; Cell senescence; Mitophagy; Signaling pathways

DOI:  https://doi.org/10.1016/bs.apcsb.2023.03.001
Vascul Pharmacol. 2023 Jul 11. pii: S1537-1891(23)00054-X. [Epub ahead of print] 107194

Prostacyclin mimetics inhibit DRP1-mediated pro-proliferative mitochondrial fragmentation in pulmonary arterial hypertension.

Jeries Abu-Hanna, Evangelos Anastasakis, Jigisha A Patel, Mohammad Mahmoud Rajab Eddama, Christopher P Denton, Jan-Willem Taanman, David Abraham, Lucie H Clapp.

  Pulmonary arterial hypertension (PAH) is a rare cardiopulmonary disorder, involving the remodelling of the small pulmonary arteries. Underlying this remodelling is the hyper-proliferation of pulmonary arterial smooth muscle cells within the medial layers of these arteries and their encroachment on the lumen. Previous studies have demonstrated an association between excessive mitochondrial fragmentation, a consequence of increased expression and post-translational activation of the mitochondrial fission protein dynamin-related protein 1 (DRP1), and pathological proliferation in PASMCs derived from PAH patients. However, the impact of prostacyclin mimetics, widely used in the treatment of PAH, on this pathological mitochondrial fragmentation remains unexplored. We hypothesise that these agents, which are known to attenuate the proliferative phenotype of PAH PASMCs, do so in part by inhibiting mitochondrial fragmentation. In this study, we confirmed the previously reported increase in DRP1-mediated mitochondrial hyper-fragmentation in PAH PASMCs. We then showed that the prostacyclin mimetic treprostinil signals via either the Gs-coupled IP or EP2 receptor to inhibit mitochondrial fragmentation and the associated hyper-proliferation in a manner analogous to the DRP1 inhibitor Mdivi-1. We also showed that treprostinil recruits either the IP or EP2 receptor to activate PKA and induce the phosphorylation of DRP1 at the inhibitory residue S637 and inhibit that at the stimulatory residue S616, both of which are suggestive of reduced DRP1 fission activity. Like treprostinil, MRE-269, an IP receptor agonist, and butaprost, an EP2 receptor agonist, attenuated DRP1-mediated mitochondrial fragmentation through PKA. We conclude that prostacyclin mimetics produce their anti-proliferative effects on PAH PASMCs in part by inhibiting DRP1-mediated mitochondrial fragmentation.

Keywords:  Dynamin-related protein 1; Mitochondria; Prostacyclin; Pulmonary arterial hypertension; Pulmonary arterial smooth muscle cells

DOI:  https://doi.org/10.1016/j.vph.2023.107194
bioRxiv. 2023 Jun 29. pii: 2023.06.28.546902. [Epub ahead of print]

High-Intensity Interval Training Attenuates Impairment in Regulatory Protein Machinery of Mitochondrial Quality Control in Skeletal Muscle of Diet-Induced Obese Mice.

James B Tincknell, Benjamin Kugler, Haley Spicuzza, Huimin Yan, Tongjian You, Kai Zou.

Mitochondrial quality control processes are essential in governing mitochondrial integrity and function. The purpose of the study was to examine the effects of 10 weeks of HIIT on the regulatory protein machinery of skeletal muscle mitochondrial quality control and whole-body glucose homeostasis in diet-induced obese mice. Male C57BL/6 mice were randomly assigned to a low-fat diet (LFD) or high-fat diet (HFD) group. After 10 weeks, HFD-fed mice were divided into sedentary and HIIT (HFD+HIIT) groups and remained on HFD for another 10 weeks (n=9/group). Graded exercise test, glucose and insulin tolerance tests, mitochondrial respiration and regulatory protein markers of mitochondrial quality control processes were determined by immunoblots. Ten weeks of HIIT enhanced ADP-stimulated mitochondrial respiration in diet-induced obese mice (P < 0.05) but did not improve whole-body insulin sensitivity. Importantly, the ratio of Drp1(Ser 616 ) over Drp1(Ser 637 ) phosphorylation, an indicator of mitochondrial fission, was attenuated in HFD-HIIT compared to HFD (-35.7%, P < 0.05). Regarding autophagy, skeletal muscle p62 content was lower in HFD group than LFD group (-35.1%, P < 0.05), however, such reduction was disappeared in HFD+HIIT group. In addition, LC3B II/I ratio was higher in HFD than LFD group (15.5%, P < 0.05) but was ameliorated in HFD+HIIT group (-29.9%, P < 0.05). Overall, our study demonstrated that 10 weeks of HIIT was effective in improving skeletal muscle mitochondrial respiration and the regulatory protein machinery of mitochondrial quality control in diet-induced obese mice through the alterations of mitochondrial fission protein Drp1 activity and p62/LC3B-mediated regulatory machinery of autophagy.

DOI: https://doi.org/10.1101/2023.06.28.546902
Kidney Res Clin Pract. 2023 May 22.

Mitochondrial quality control and its emerging role in the pathogenesis of diabetic kidney disease.

Jihyun Baek, Yu Ho Lee, Hye Yun Jeong, So-Young Lee.

  Most eukaryotic cells have mitochondrial networks that can change in shape, distribution, and size depending on cellular metabolic demands and environments. Mitochondrial quality control is critical for various mitochondrial functions including energy production, redox homeostasis, intracellular calcium handling, cell differentiation, proliferation, and cell death. Quality control mechanisms within mitochondria consist of antioxidant defenses, protein quality control, DNA damage repair systems, mitochondrial fusion and fission, mitophagy, and mitochondrial biogenesis. Defects in mitochondrial quality control and disruption of mitochondrial homeostasis are common characteristics of various kidney cell types under hyperglycemic conditions. Such defects contribute to diabetes-induced pathologies in renal tubular cells, podocytes, endothelial cells, and immune cells. In this review, we focus on the roles of mitochondrial quality control in diabetic kidney disease pathogenesis and discuss current research evidence and future directions.

Keywords:  Diabetic kidney disease; Endothelial cells; Immune cells; Mitochondrial quality control; Podocytes; Renal tubular cells

DOI:  https://doi.org/10.23876/j.krcp.22.233
Oncogene. 2023 Jul 11.

Notch signaling regulates a metabolic switch through inhibiting PGC-1α and mitochondrial biogenesis in dedifferentiated liposarcoma.

Pei-Chieh Tien, Xiyue Chen, Bennett D Elzey, Raphael E Pollock, Shihuan Kuang.

Human dedifferentiated liposarcoma (DDLPS) is a rare but lethal cancer with no driver mutations being identified, hampering the development of targeted therapies. We and others recently reported that constitutive activation of Notch signaling through overexpression of the Notch1 intracellular domain (NICDOE) in murine adipocytes leads to tumors resembling human DDLPS. However, the mechanisms underlying the oncogenic functions of Notch activation in DDLPS remains unclear. Here, we show that Notch signaling is activated in a subset of human DDLPS and correlates with poor prognosis and expression of MDM2, a defining marker of DDLPS. Metabolic analyses reveal that murine NICDOE DDLPS cells exhibit markedly reduced mitochondrial respiration and increased glycolysis, mimicking the Warburg effect. This metabolic switch is associated with diminished expression of peroxisome proliferator-activated receptor gamma coactivator 1α (Ppargc1a, encoding PGC-1α protein), a master regulator of mitochondrial biogenesis. Genetic ablation of the NICDOE cassette rescues the expression of PGC-1α and mitochondrial respiration. Similarly, overexpression of PGC-1α is sufficient to rescue mitochondria biogenesis, inhibit the growth and promote adipogenic differentiation of DDLPS cells. Together, these data demonstrate that Notch activation inhibits PGC-1α to suppress mitochondrial biogenesis and drive a metabolic switch in DDLPS.

DOI: https://doi.org/10.1038/s41388-023-02768-6
bioRxiv. 2023 Jun 26. pii: 2023.06.25.546311. [Epub ahead of print]

Lysosomal mitochondrial interaction promotes tumor growth in squamous cell carcinoma of the head and neck.

Avani Gopalkrishnan, Nathaniel Wang, Silvia Cruz-Rangel, Abdul Yassin- Kassab, Sruti Shiva, Chareeni Kurukulasuriya, Satdarshan P Monga, Ralph J DeBerardinis, Kirill Kiselyov, Umamaheswar Duvvuri.

Tumor growth and proliferation are regulated by numerous mechanisms. Communication between intracellular organelles has recently been shown to regulate cellular proliferation and fitness. The way lysosomes and mitochondria communicate with each other (lysosomal/mitochondrial interaction) is emerging as a major determinant of tumor proliferation and growth. About 30% of squamous carcinomas (including squamous cell carcinoma of the head and neck, SCCHN) overexpress TMEM16A, a calcium-activated chloride channel, which promotes cellular growth and negatively correlates with patient survival. TMEM16A has recently been shown to drive lysosomal biogenesis, but its impact on mitochondrial function is unclear. Here, we show that (1) patients with high TMEM16A SCCHN display increased mitochondrial content specifically complex I; (2) In vitro and in vivo models uniquely depend on mitochondrial complex I activity for growth and survival; (3) β-catenin/NRF2 signaling is a critical linchpin that drives mitochondrial biogenesis, and (4) mitochondrial complex I and lysosomal function are codependent for proliferation. Taken together, our data demonstrate that LMI drives tumor proliferation and facilitates a functional interaction between lysosomes and mitochondria. Therefore, inhibition of LMI may serve as a therapeutic strategy for patients with SCCHN.

DOI: https://doi.org/10.1101/2023.06.25.546311
bioRxiv. 2023 Jun 26. pii: 2023.06.23.546087. [Epub ahead of print]

Defects in Mitochondrial Biogenesis Drive Mitochondrial Alterations in PINK1-deficient Human Dopamine Neurons.

Hu Wang, Rong Chen, Liming Xiao, Manoj Kumar, Jesús Acevedo-Cintrón, Joanna Siuda, Dariusz Koziorowski, Zbigniew K Wszolek, Valina L Dawson, Ted M Dawson.

Mutations and loss of activity in the protein kinase PINK1 play a role in the pathogenesis of Parkinson's disease (PD). PINK1 regulates many aspects of mitochondrial quality control including mitochondrial autophagy (mitophagy), fission, fusion, transport, and biogenesis. Defects in mitophagy are though to play a predominant role in the loss of dopamine (DA) neurons in PD. Here we show that, although there are defects in mitophagy in human DA neurons lacking PINK1, mitochondrial deficits induced by the absence of PINK1 are primarily due to defects in mitochondrial biogenesis. Upregulation of PARIS and the subsequent down regulation of PGC-1α accounts for the mitochondrial biogenesis defects. CRISPR/Cas9 knockdown of PARIS completely restores the mitochondrial biogenesis defects and mitochondrial function without impacting the deficits in mitophagy due to the absence of PINK1. These results highlight the importance mitochondrial biogenesis in the pathogenesis of PD due to inactivation or loss of PINK1 in human DA neurons.

DOI: https://doi.org/10.1101/2023.06.23.546087