bims-mikwok 2021-12-12 papers

bims-mikwok

Biomed News

on Mitochondrial quality control

Issue of 2021‒12‒12
ten papers selected by
Avinash N. Mukkala, University of Toronto

Mitophagy in aging and longevity.
MITOL-mediated DRP1 ubiquitylation and degradation promotes mitochondrial hyperfusion in CMT2A-linked MFN2 mutant.
Role of Mitochondrial Therapy for Ischemic-Reperfusion Injury and Acute Kidney Injury.
MIROs and DRP1 drive mitochondrial-derived vesicle biogenesis and promote quality control.
CDK9 inhibition blocks the initiation of PINK1-PRKN-mediated mitophagy by regulating the SIRT1-FOXO3-BNIP3 axis and enhances the therapeutic effects involving mitochondrial dysfunction in hepatocellular carcinoma.
Mitochondria Metabolomics Reveals a Role of β-Nicotinamide Mononucleotide Metabolism in Mitochondrial DNA Replication.
Knocking down peroxiredoxin 6 aggravates cerebral ischemia-reperfusion injury by enhancing mitophagy.
Acetoacetate protects macrophages from lactic acidosis-induced mitochondrial dysfunction by metabolic reprograming.
Molecular mechanisms and consequences of mitochondrial permeability transition.
Molecular species selectivity of lipid transport creates a mitochondrial sink for di-unsaturated phospholipids.

IUBMB Life. 2021 Dec 10.

Mitophagy in aging and longevity.

Jing Guo, Wei-Chung Chiang.

  The clearance of damaged or unwanted mitochondria by autophagy (also known as mitophagy) is a mitochondrial quality control mechanism postulated to play an essential role in cellular homeostasis, metabolism, and development and confers protection against a wide range of diseases. Proper removal of damaged or unwanted mitochondria is essential for organismal health. Defects in mitophagy are associated with Parkinson's, Alzheimer's disease, cancer, and other degenerative disorders. Mitochondria regulate organismal fitness and longevity via multiple pathways, including cellular senescence, stem cell function, inflammation, mitochondrial unfolded protein response (mtUPR), and bioenergetics. Thus, mitophagy is postulated to be pivotal for maintaining organismal healthspan and lifespan and the protection against aged-related degeneration. In this review, we will summarize recent understanding of the mechanism of mitophagy and aspects of mitochondrial functions. We will focus on mitochondria-related cellular processes that are linked to aging and examine current genetic evidence that supports the hypothesis that mitophagy is a pro-longevity mechanism.

Keywords:  aging; longevity; mitophagy

DOI:  https://doi.org/10.1002/iub.2585
J Cell Sci. 2021 Dec 06. pii: jcs.257808. [Epub ahead of print]

MITOL-mediated DRP1 ubiquitylation and degradation promotes mitochondrial hyperfusion in CMT2A-linked MFN2 mutant.

Rajdeep Das, Izaz Monir Kamal, Subhrangshu Das, Saikat Chakrabarti, Oishee Chakrabarti.

  Mutations in Mitofusin2 (MFN2), associated with the pathology of the debilitating neuropathy, Charcot-Marie-Tooth type 2A (CMT2A) are known to alter mitochondrial morphology. One such abundant MFN2 mutant, R364W results in the generation of elongated, interconnected mitochondria. However, the mechanism leading to this mitochondrial aberration remains poorly understood. Here we show that mitochondrial hyperfusion in the presence of R364W-MFN2 is due to increased degradation of DRP1. The Ubiquitin E3 ligase MITOL is known to ubiquitylate both MFN2 and DRP1. Interaction with and its subsequent ubiquitylation by MITOL is stronger in presence of WT-MFN2 than R364W-MFN2. This differential interaction of MITOL with MFN2 in the presence of R364W-MFN2 renders the ligase more available for DRP1 ubiquitylation. Multimonoubiquitylation and proteasomal degradation of DRP1 in R364W-MFN2 cells in the presence of MITOL eventually leads to mitochondrial hyperfusion. Here we provide a mechanistic insight into mitochondrial hyperfusion, while also reporting that MFN2 can indirectly modulate DRP1 - an effect not shown before.

Keywords:  CMT2A-linked MFN2 mutant; DRP1; MITOL; Mitochondrial hyperfusion; Ubiquitylation

DOI:  https://doi.org/10.1242/jcs.257808
Nephron. 2021 Dec 09. 1-6

Role of Mitochondrial Therapy for Ischemic-Reperfusion Injury and Acute Kidney Injury.

Navjot Pabla, Amandeep Bajwa.

  Acute kidney injury (AKI) is a common clinical disorder associated with decline in renal function because of ischemic and nephrotoxic insults. The pathophysiology of AKI involves multiple cellular mechanisms, such as kidney parenchymal cell (epithelial and endothelial) dysfunction and immune-cell infiltration. Mitochondrial injury which causes ATP depletion and triggers apoptosis and necrosis is at the heart of ischemia reperfusion injury (IRI). Pharmacological (SS-31 or MitoQ), cellular (dendritic cells or mesenchymal stem cells), or genetic strategies that either directly or indirectly preserve mitochondrial integrity and function have been shown to mitigate IRI-linked AKI in preclinical models. Interestingly, isolated mitochondria have been recently shown to be taken up by various mammalian cells resulting in incorporation of transplanted mitochondria into the endogenous mitochondrial network of recipient cells and contributing to protection from ischemic injury in various preclinical models of ischemia including the heart, liver, and kidneys. The mini review summarizes the current available therapeutic strategies that improve kidney function by targeting mitochondria health.

Keywords:  Acute kidney injury; Ischemia reperfusion injury; Mitochondria

DOI:  https://doi.org/10.1159/000520698
Nat Cell Biol. 2021 Dec 06.

MIROs and DRP1 drive mitochondrial-derived vesicle biogenesis and promote quality control.

Tim König, Hendrik Nolte, Mari J Aaltonen, Takashi Tatsuta, Michiel Krols, Thomas Stroh, Thomas Langer, Heidi M McBride.

Mitochondrial-derived vesicles (MDVs) are implicated in diverse physiological processes-for example, mitochondrial quality control-and are linked to various neurodegenerative diseases. However, their specific cargo composition and complex molecular biogenesis are still unknown. Here we report the proteome and lipidome of steady-state TOMM20+ MDVs. We identified 107 high-confidence MDV cargoes, which include all β-barrel proteins and the TOM import complex. MDV cargoes are delivered as fully assembled complexes to lysosomes, thus representing a selective mitochondrial quality control mechanism for multi-subunit complexes, including the TOM machinery. Moreover, we define key biogenesis steps of phosphatidic acid-enriched MDVs starting with the MIRO1/2-dependent formation of thin membrane protrusions pulled along microtubule filaments, followed by MID49/MID51/MFF-dependent recruitment of the dynamin family GTPase DRP1 and finally DRP1-dependent scission. In summary, we define the function of MDVs in mitochondrial quality control and present a mechanistic model for global GTPase-driven MDV biogenesis.

DOI: https://doi.org/10.1038/s41556-021-00798-4
Autophagy. 2021 Dec 10. 1-19

CDK9 inhibition blocks the initiation of PINK1-PRKN-mediated mitophagy by regulating the SIRT1-FOXO3-BNIP3 axis and enhances the therapeutic effects involving mitochondrial dysfunction in hepatocellular carcinoma.

Jingyue Yao, Jubo Wang, Ye Xu, Qinglong Guo, Yuening Sun, Jian Liu, Sichan Li, Yongjian Guo, Libin Wei.

  Mitophagy is a type of selective macroautophagy/autophagy that degrades dysfunctional or excessive mitochondria. Regulation of this process is critical for maintaining cellular homeostasis and has been closely implicated in acquired drug resistance. However, the regulatory mechanisms and influences of mitophagy in cancer are still unclear. Here, we reported that inhibition of CDK9 blocked PINK1-PRKN-mediated mitophagy in HCC (hepatocellular carcinoma) by interrupting mitophagy initiation. We demonstrated that CDK9 inhibitors promoted dephosphorylation of SIRT1 and promoted FOXO3 protein degradation, which was regulated by its acetylation, leading to the transcriptional repression of FOXO3-driven BNIP3 and impairing the BNIP3-mediated stability of the PINK1 protein. Lysosomal degradation inhibitors could not rescue mitophagy flux blocked by CDK9 inhibitors. Thus, CDK9 inhibitors inactivated the SIRT1-FOXO3-BNIP3 axis and PINK1-PRKN pathway to subsequently block mitophagy initiation. Moreover, CDK9 inhibitors facilitated mitochondrial dysfunction. The dual effects of CDK9 inhibitors resulted in the destruction of mitochondrial homeostasis and cell death in HCC. Importantly, a novel CDK9 inhibitor, oroxylin A (OA), from Scutellaria baicalensis was investigated, and it showed strong therapeutic potential against HCC and a striking capacity to overcome drug resistance by downregulating PINK1-PRKN-mediated mitophagy. Additionally, because of the moderate and controlled inhibition of CDK9, OA not led to extreme repression of general transcription and appeared to overcome the inconsistent anti-HCC efficacy and high normal tissue toxicity that was associated with existing CDK9 inhibitors. All of the findings reveal that mitophagy disruption is a promising strategy for HCC treatment and OA is a potential candidate for the development of mitophagy inhibitors.Abbreviations: BNIP3: BCL2 interacting protein 3; CCCP: carbonyl cyanide p-trichloromethoxy-phenylhydrazone; CDK9: cyclin dependent kinase 9; CHX: cycloheximide; CQ, chloroquine; DFP: deferiprone; DOX: doxorubicin; EBSS: Earle's balanced salt solution; E64d: aloxistatin; FOXO3: forkhead box O3; HCC: hepatocellular carcinoma; HepG2/ADR: adriamycin-resistant HepG2 cells; MMP: mitochondrial membrane potential; mito-Keima: mitochondria-targeted and pH-sensitive fluorescent protein; MitoSOX: mitochondrial reactive oxygen species; OA: oroxylin A; PB: phosphate buffer; PDX: patient-derived tumor xenograft; PINK1: PTEN induced kinase 1; POLR2A: RNA polymerase II subunit A; p-POLR2A-S2: Ser2 phosphorylation of RNA polymerase II subunit A; PRKN: parkin RBR E3 ubiquitin protein ligase; SIRT1: sirtuin 1.

Keywords:  CDK9; PINK1-PRKN; drug resistance; hepatocellular carcinoma; mitophagy

DOI:  https://doi.org/10.1080/15548627.2021.2007027
J Biochem. 2021 Dec 04. pii: mvab136. [Epub ahead of print]

Mitochondria Metabolomics Reveals a Role of β-Nicotinamide Mononucleotide Metabolism in Mitochondrial DNA Replication.

Tomoko Nomiyama, Daiki Setoyama, Takehiro Yasukawa, Dongchon Kang.

  Mitochondrial DNA (mtDNA) replication is tightly regulated and necessary for cellular homeostasis; however, its relationship with mitochondrial metabolism remains unclear. Advances in metabolomics integrated with the rapid isolation of mitochondria will allow for remarkable progress in analyzing mitochondrial metabolism. Here, we propose a novel methodology for mitochondria-targeted metabolomics, which employs a quick isolation procedure using a hemolytic toxin from Streptococcus pyogenes streptolysin O (SLO). SLO-isolation of mitochondria from cultured HEK293 cells is time- and labor-saving for simultaneous multi-sample processing and has been applied to various other cell lines in this study. Furthermore, our method can detect the time-dependent reduction in mitochondrial ATP in response to a glycolytic inhibitor 2-deoxyglucose, indicating the suitability to prepare metabolite analysis-competent mitochondria. Using this methodology, we searched for specific mitochondrial metabolites associated with mtDNA replication activation, and nucleotides and NAD+ were identified to be prominently altered. Most notably, treatment of β-Nicotinamide Mononucleotide (β-NMN), a precursor of NAD+, to HEK293 cells activated and improved the rate of mtDNA replication by increasing nucleotides in mitochondria and decreasing their degradation products: nucleosides. Our results suggest that β-NMN metabolism play a role in supporting mtDNA replication by maintaining the nucleotide pool balance in the mitochondria.

Keywords:  beta-nicotinamide mononucleotide (β-NMN); metabolomics; mitochondrial DNA; nucleotide metabolism; streptolysin O

DOI:  https://doi.org/10.1093/jb/mvab136
Neuroscience. 2021 Dec 01. pii: S0306-4522(21)00610-2. [Epub ahead of print]

Knocking down peroxiredoxin 6 aggravates cerebral ischemia-reperfusion injury by enhancing mitophagy.

Toushen Hong, Yang Zhou, Li Peng, Xiaoying Wu, Yixin Li, Yumei Li, Yong Zhao.

  Cerebral ischemia-reperfusion injury(IRI) is caused by reperfusion following ischemia. Mitophagy is closely related to cerebral ischemia-reperfusion injury. mitophagy disorder or excess may be harmful and lead to neuronal apoptosis. Peroxiredoxin 6 (PRDX6) is an antioxidant protein and plays an important role in ischemic stroke. However, the relationship between PRDX6 and mitophagy is not clear at present. In order to explore and solve this problem. We have established a middle cerebral artery occlusion(MCAO) model of cerebral ischemia-reperfusion in SD rats and knockdown PRDX6 and PINK1 with lentivirus.Knocking down PRDX6 led to further aggravation of cerebral ischemia-reperfusion injury. Our research found that knockdown PRDX6 increased the expression of mitophagy-related and apoptosis-related proteins. Knocking down PINK1 relieved mitophagy and apoptosis caused by knocking down PRDX6. In conclusion, knockdown of PRDX6 could aggravate cerebral ischemia-reperfusion injury by enhancing PINK1/PARKIN pathway mediated mitophagy, and this effect could increase neuronal apoptosis.

Keywords:  Peroxiredoxin 6; apoptosis; cerebral ischemia-reperfusion injury; mitophagy

DOI:  https://doi.org/10.1016/j.neuroscience.2021.11.043
Nat Commun. 2021 Dec 08. 12(1): 7115

Acetoacetate protects macrophages from lactic acidosis-induced mitochondrial dysfunction by metabolic reprograming.

Clément Adam, Léa Paolini, Naïg Gueguen, Guillaume Mabilleau, Laurence Preisser, Simon Blanchard, Pascale Pignon, Florence Manero, Morgane Le Mao, Alain Morel, Pascal Reynier, Céline Beauvillain, Yves Delneste, Vincent Procaccio, Pascale Jeannin.

Lactic acidosis, the extracellular accumulation of lactate and protons, is a consequence of increased glycolysis triggered by insufficient oxygen supply to tissues. Macrophages are able to differentiate from monocytes under such acidotic conditions, and remain active in order to resolve the underlying injury. Here we show that, in lactic acidosis, human monocytes differentiating into macrophages are characterized by depolarized mitochondria, transient reduction of mitochondrial mass due to mitophagy, and a significant decrease in nutrient absorption. These metabolic changes, resembling pseudostarvation, result from the low extracellular pH rather than from the lactosis component, and render these cells dependent on autophagy for survival. Meanwhile, acetoacetate, a natural metabolite produced by the liver, is utilized by monocytes/macrophages as an alternative fuel to mitigate lactic acidosis-induced pseudostarvation, as evidenced by retained mitochondrial integrity and function, retained nutrient uptake, and survival without the need of autophagy. Our results thus show that acetoacetate may increase tissue tolerance to sustained lactic acidosis.

DOI: https://doi.org/10.1038/s41467-021-27426-x
Nat Rev Mol Cell Biol. 2021 Dec 08.

Molecular mechanisms and consequences of mitochondrial permeability transition.

Massimo Bonora, Carlotta Giorgi, Paolo Pinton.

Mitochondrial permeability transition (mPT) is a phenomenon that abruptly causes the flux of low molecular weight solutes (molecular weight up to 1,500) across the generally impermeable inner mitochondrial membrane. The mPT is mediated by the so-called mitochondrial permeability transition pore (mPTP), a supramolecular entity assembled at the interface of the inner and outer mitochondrial membranes. In contrast to mitochondrial outer membrane permeabilization, which mostly activates apoptosis, mPT can trigger different cellular responses, from the physiological regulation of mitophagy to the activation of apoptosis or necrosis. Although there are several molecular candidates for the mPTP, its molecular nature remains contentious. This lack of molecular data was a significant setback that prevented mechanistic insight into the mPTP, pharmacological targeting and the generation of informative animal models. In recent years, experimental evidence has highlighted mitochondrial F1Fo ATP synthase as a participant in mPTP formation, although a molecular model for its transition to the mPTP is still lacking. Recently, the resolution of the F1Fo ATP synthase structure by cryogenic electron microscopy led to a model for mPTP gating. The elusive molecular nature of the mPTP is now being clarified, marking a turning point for understanding mitochondrial biology and its pathophysiological ramifications. This Review provides an up-to-date reference for the understanding of the mammalian mPTP and its cellular functions. We review current insights into the molecular mechanisms of mPT and validated observations - from studies in vivo or in artificial membranes - on mPTP activity and functions. We end with a discussion of the contribution of the mPTP to human disease. Throughout the Review, we highlight the multiple unanswered questions and, when applicable, we also provide alternative interpretations of the recent discoveries.

DOI: https://doi.org/10.1038/s41580-021-00433-y
EMBO J. 2021 Dec 07. e106837

Molecular species selectivity of lipid transport creates a mitochondrial sink for di-unsaturated phospholipids.

Mike F Renne, Xue Bao, Margriet Wj Hokken, Adolf S Bierhuizen, Martin Hermansson, Richard R Sprenger, Tom A Ewing, Xiao Ma, Ruud C Cox, Jos F Brouwers, Cedric H De Smet, Christer S Ejsing, Anton Ipm de Kroon.

  Mitochondria depend on the import of phospholipid precursors for the biosynthesis of phosphatidylethanolamine (PE) and cardiolipin, yet the mechanism of their transport remains elusive. A dynamic lipidomics approach revealed that mitochondria preferentially import di-unsaturated phosphatidylserine (PS) for subsequent conversion to PE by the mitochondrial PS decarboxylase Psd1p. Several protein complexes tethering mitochondria to the endomembrane system have been implicated in lipid transport in yeast, including the endoplasmic reticulum (ER)-mitochondrial encounter structure (ERMES), ER-membrane complex (EMC), and the vacuole and mitochondria patch (vCLAMP). By limiting the availability of unsaturated phospholipids, we created conditions to investigate the mechanism of lipid transfer and the contributions of the tethering complexes in vivo. Under these conditions, inactivation of ERMES components or of the vCLAMP component Vps39p exacerbated accumulation of saturated lipid acyl chains, indicating that ERMES and Vps39p contribute to the mitochondrial sink for unsaturated acyl chains by mediating transfer of di-unsaturated phospholipids. These results support the concept that intermembrane lipid flow is rate-limited by molecular species-dependent lipid efflux from the donor membrane and driven by the lipid species' concentration gradient between donor and acceptor membrane.

Keywords:  lipid transport; membrane contact sites; membrane lipid homeostasis; membrane lipid unsaturation; mitochondria

DOI:  https://doi.org/10.15252/embj.2020106837