bims-mikwok 2023-01-29 papers

bims-mikwok

Biomed News

on Mitochondrial quality control

Issue of 2023–01–29
fiveteen papers selected by
Avinash N. Mukkala, University of Toronto

Endosomal-dependent mitophagy coordinates mitochondrial nucleoid and mtDNA elimination.
PRKN/parkin-mediated mitophagy is induced by the probiotics Saccharomyces boulardii and Lactococcus lactis.
Mechanisms behind therapeutic potentials of mesenchymal stem cell mitochondria transfer/delivery.
Inhibition of Drp1-dependent mitochondrial fission by natural compounds as a therapeutic strategy for organ injuries.
Mitofusin 1 and 2 differentially regulate mitochondrial function underlying Ca2+ signaling and proliferation in rat aortic smooth muscle cells.
Mitochondrial transplant after ischemia reperfusion promotes cellular salvage and improves lung function during ex-vivo lung perfusion.
Sigma-1 receptor is involved in modification of ER-mitochondria proximity and Ca2+ homeostasis in cardiomyocytes.
The selective autophagy adaptor p62/SQSTM1 forms phase condensates regulated by HSP27 that facilitate the clearance of damaged lysosomes via lysophagy.
Severe acute respiratory syndrome coronaviruses contributing to mitochondrial dysfunction: Implications for post-COVID complications.
Small heat shock proteins operate as molecular chaperones in the mitochondrial intermembrane space.
Mitochondrial complexome reveals quality-control pathways of protein import.
MORN4 protects cardiomyocytes against ischemic injury via MFN2-mediated mitochondrial dynamics and mitophagy.
Mitochondrial NAD kinase in health and disease.
Mitochondrial remodelling is essential for female germ cell differentiation and survival.
Nucleolin protects cardiomyocytes by upregulating PGC-1α and promoting mitochondrial biogenesis in LPS-induced myocardial injury.

Autophagy. 2023 Jan 24.

Endosomal-dependent mitophagy coordinates mitochondrial nucleoid and mtDNA elimination.

Ayesha Sen, Julia Boix, David Pla-Martín.

  Mitophagy and its variants are considered important salvage pathways to remove dysfunctional mitochondria. Non-canonical mitophagy, independent of autophagosome formation and including endosomal-dependent mitophagy, operate upon specific injury. In a recent paper, we describe a new mechanism where, upon mtDNA damage, mitochondrial nucleoids are eliminated via an endosomal-mitophagy pathway. Using proximity proteomics, we identified the proteins required for elimination of mutated mitochondrial nucleoids from the mitochondrial matrix. Among them, ATAD3 and SAMM50 control cristae architecture and nucleoid interaction, necessary for mtDNA extraction. In the mitochondrial outer membrane, SAMM50 coordinates with the retromer protein VPS35 to sequester mtDNA in endosomes and guide them towards elimination, thus avoiding the activation of an exacerbated immune response. Here, we summarize our findings and examine how this newly described pathway contributes to our understanding of mtDNA quality control.

Keywords:  - mitophagy; endosomes; mtDNA

DOI:  https://doi.org/10.1080/15548627.2023.2170959
Autophagy. 2023 Jan 28.

PRKN/parkin-mediated mitophagy is induced by the probiotics Saccharomyces boulardii and Lactococcus lactis.

Peter John Hawrysh, Jinghua Gao, Stephanie Tan, Amy Oh, Justin Nodwell, Thomas A Tompkins, G Angus McQuibban.

  Mitochondrial impairment is a hallmark feature of neurodegenerative disorders, such as Parkinson disease, and PRKN/parkin-mediated mitophagy serves to remove unhealthy mitochondria from cells. Notably, probiotics are used to alleviate several symptoms of Parkinson disease including impaired locomotion and neurodegeneration in preclinical studies and constipation in clinical trials. There is some evidence to suggest that probiotics can modulate mitochondrial quality control pathways. In this study, we screened 49 probiotic strains and tested distinct stages of mitophagy to determine whether probiotic treatment could upregulate mitophagy in cells undergoing mitochondrial stress. We found two probiotics, Saccharomyces boulardii and Lactococcus lactis, that upregulated mitochondrial PRKN recruitment, phospho-ubiquitination, and MFN degradation in our cellular assays. Administration of these strains to Drosophila that were exposed to paraquat, a mitochondrial toxin, resulted in improved longevity and motor function. Further, we directly observed increased lysosomal degradation of dysfunctional mitochondria in the treated Drosophila brains. These effects were replicated in vitro and in vivo with supra-physiological concentrations of exogenous soluble factors that are released by probiotics in cultures grown under laboratory conditions. We identified methyl-isoquinoline-6-carboxylate as one candidate molecule, which upregulates mitochondrial PRKN recruitment, phospho-ubiquitination, MFN degradation, and lysosomal degradation of damaged mitochondria. Addition of methyl-isoquinoline-6-carboxylate to the fly food restored motor function to paraquat-treated Drosophila. These data suggest a novel mechanism that is facilitated by probiotics to stimulate mitophagy through a PRKN-dependent pathway, which could explain the potential therapeutic benefit of probiotic administration to patients with Parkinson disease.

Keywords:  Drosophila; PRKN/parkin; Parkinson disease; melanoxadin; methyl-isoquinoline-6-carboxylate; mitochondria; picolinic acid

DOI:  https://doi.org/10.1080/15548627.2023.2172873
J Control Release. 2023 Jan 24. pii: S0168-3659(23)00068-8. [Epub ahead of print]

Mechanisms behind therapeutic potentials of mesenchymal stem cell mitochondria transfer/delivery.

Kosar Malekpour, Ali Hazrati, Sara Soudi, Seyed Mahmoud Hashemi.

  Mesenchymal stromal/stem cells (MSCs) perform their therapeutic effects through various mechanisms, including their ability to differentiate, producing different growth factors, immunomodulatory factors, and extracellular vesicles (EVs). In addition to the mentioned mechanisms, a new aspect of the therapeutic potential of MSCs has recently been noticed, which occurs through mitochondrial transfer. Various methods of MSCs mitochondria transfer have been used in studies to benefit from their therapeutic potential. Among these methods, mitochondrial transfer after MSCs transplantation in cell-to-cell contact, EVs-mediated transfer of mitochondria, and the use of MSCs isolated mitochondria (MSCs-mt) are well studied. Pathological conditions can affect the cells in the damaged microenvironment and lead to cells mitochondrial damage. Since the defect in the mitochondrial function of the cell leads to a decrease in ATP production and the subsequent cell death, restoring the mitochondrial content, functions, and hemostasis can affect the functions of the damaged cell. Various studies show that the transfer of MSCs mitochondria to other cells can affect vital processes such as proliferation, differentiation, cell metabolism, inflammatory responses, cell senescence, cell stress, and cell migration. These changes in cell attributes and behavior are very important for therapeutic purposes. For this reason, their investigation can play a significant role in the direction of the researchers'.

Keywords:  Cell therapy; Extracellular vesicles; Immune cells; MSCs; Mitochondria; Regenerative medicine

DOI:  https://doi.org/10.1016/j.jconrel.2023.01.059
Pharmacol Res. 2023 Jan 20. pii: S1043-6618(23)00028-2. [Epub ahead of print]188 106672

Inhibition of Drp1-dependent mitochondrial fission by natural compounds as a therapeutic strategy for organ injuries.

Sohrab Rahmani, Ali Roohbakhsh, Gholamreza Karimi.

  Mitochondria are morphologically dynamic organelles frequently undergoing fission and fusion processes that regulate mitochondrial integrity and bioenergetics. These processes are considered critical for cell survival. The mitochondrial fission process regulates mitochondrial biogenesis and mitophagy. It is associated with apoptosis, while mitochondrial fusion controls the accurate distribution of mitochondrial DNA and metabolic substances across the mitochondria. Excessive mitochondrial fission results in mitochondrial structural changes, dysfunction, and cell damage. Accumulating evidence demonstrates that mitochondrial dynamics affect neurodegenerative and cardiovascular diseases along with several other diseases. Biological molecules regulating the process of mitochondrial fission are potential targets for developing therapeutic agents. Many natural products target the dynamin-related protein 1 (Drp1)-dependent mitochondrial fission pathway, and their inhibitory effects ameliorate mitochondrial fragmentation. In this article, we reviewed the research literature that describes Drp1-dependent inhibition as a mechanism for the protective effects of natural compounds.

Keywords:  Apoptosis; Dynamin-related protein 1; Fission inhibitors; Free radical production; Herbal medicine; Mitochondrial fission; Mitochondrial fusion; Natural compound

DOI:  https://doi.org/10.1016/j.phrs.2023.106672
Biochem Biophys Res Commun. 2023 Jan 16. pii: S0006-291X(23)00075-X. [Epub ahead of print]645 137-146

Mitofusin 1 and 2 differentially regulate mitochondrial function underlying Ca2+ signaling and proliferation in rat aortic smooth muscle cells.

Sou Inagaki, Yoshiaki Suzuki, Keisuke Kawasaki, Rubii Kondo, Yuji Imaizumi, Hisao Yamamura.

  Mitochondria play a substantial role in cytosolic Ca2+ buffering and energy metabolism. We recently demonstrated that mitofusin 2 (Mfn2) regulated Ca2+ signaling by tethering mitochondria and sarcoplasmic reticulum (SR), and thus, facilitated mitochondrial function and the proliferation of vascular smooth muscle cells (VSMCs). However, the physiological role of mitofusin 1 (Mfn1) on Ca2+ signaling and mitochondrial function remains unclear. Herein, the roles of Mfn1 and Mfn2 in mitochondrial function underlying Ca2+ signaling, ATP production, and cell proliferation were examined in rat aortic smooth muscle A10 cells. Following an arginine vasopressin-induced increase in cytosolic Ca2+ concentration ([Ca2+]cyt), Mfn2 siRNA (siMfn2) reduced cytosolic Ca2+ removal and mitochondrial Ca2+ uptake. However, Mfn1 siRNA (siMfn1) attenuated mitochondrial Ca2+ uptake, facilitated Ca2+ removal from mitochondria, and resulted in increased [Ca2+]cyt, which was mediated by the downregulation of mitochondrial Ca2+ uniporter (MCU) expression and the upregulation of mitochondrial Na+/Ca2+ exchanger (NCLX) expression. Furthermore, siMfn1 increased the mitochondrial membrane potential, ATP production by adenine nucleotide translocase (ANT), and cell proliferation, whereas siMfn2 exhibited the opposite responses. In conclusion, Mfn1 modulates the expressions of MCU, NCLX, and ANT, and Mfn2 tethers mitochondria to SR, which demonstrates their different mitochondrial functions for Ca2+ signaling, ATP production, and the proliferation of VSMCs.

Keywords:  Calcium; Mitochondria; Mitofusin; Proliferation; Sarcoplasmic reticulum; Smooth muscle

DOI:  https://doi.org/10.1016/j.bbrc.2023.01.044
J Heart Lung Transplant. 2023 Jan 11. pii: S1053-2498(23)00002-5. [Epub ahead of print]

Mitochondrial transplant after ischemia reperfusion promotes cellular salvage and improves lung function during ex-vivo lung perfusion.

Caryn M Cloer, Christopher S Givens, Lakisha K Buie, Lauren K Rochelle, Yi-Tzu Lin, Sam Popa, Randolph V M Shelton, James Zhan, Tyler R Zimmerman, Bria G Jones, Zion Lesesne, Sarah S Hogan, Thomas H Petersen.

BACKGROUND: In lung transplantation, ischemia-reperfusion injury associated with mitochondrial damage can lead to graft rejection. Intact, exogenous mitochondria provide a unique treatment option to salvage damaged cells within lung tissue.
METHODS: We developed a novel method to freeze and store allogeneic mitochondria isolated from porcine heart tissue. Stored mitochondria were injected into a model of induced ischemia-reperfusion injury using porcine ex-vivo lung perfusion. Treatment benefits to immune modulation, antioxidant defense, and cellular salvage were evaluated. These findings were corroborated in human lungs undergoing ex-vivo lung perfusion. Lung tissue homogenate and primary lung endothelial cells were then used to address underlying mechanisms.
RESULTS: Following cold ischemia, mitochondrial transplant reduced lung pulmonary vascular resistance and tissue pro-inflammatory signaling and cytokine secretion. Further, exogenous mitochondria reduced reactive oxygen species by-products and promoted glutathione synthesis, thereby salvaging cell viability. These results were confirmed in a human model of ex-vivo lung perfusion wherein transplanted mitochondria decreased tissue oxidative and inflammatory signaling, improving lung function. We demonstrate that transplanted mitochondria induce autophagy and suggest that bolstered autophagy may act upstream of the anti-inflammatory and antioxidant benefits. Importantly, chemical inhibitors of the MEK autophagy pathway blunted the favorable effects of mitochondrial transplant.
CONCLUSIONS: These data provide direct evidence that mitochondrial transplant improves cellular health and lung function when administered during ex-vivo lung perfusion and suggest the mechanism of action may be through promotion of cellular autophagy. Data herein contribute new insights into the therapeutic potential of mitochondrial transplant to abate ischemia-reperfusion injury during lung transplant, and thus reduce graft rejection.

DOI: https://doi.org/10.1016/j.healun.2023.01.002
J Pharmacol Sci. 2023 Feb;pii: S1347-8613(22)00093-7. [Epub ahead of print]151(2): 128-133

Sigma-1 receptor is involved in modification of ER-mitochondria proximity and Ca2+ homeostasis in cardiomyocytes.

Hideaki Tagashira, Md Shenuarin Bhuiyan, Yasuharu Shinoda, Ichiro Kawahata, Tomohiro Numata, Kohji Fukunaga.

  The Sigma-1 receptor (Sigmar1) is downregulated in heart failure model mice with mitochondrial dysfunction. However, the mechanism in detail has not been investigated. In this study, we investigated the role of Sigmar1 in ER-mitochondria proximity using Sigmar1-knockdown or -overexpressed neonatal rat ventricular myocytes (NRVMs). The endothelin-1 (ET-1)-induced cardiomyocyte hypertrophy was aggravated with the dysregulation of mitochondrial function and ER-mitochondrial junctional formation in Sigmar1-knockdown NRVMs, whereas improved in Sigmar1 overexpressed NRVMs. Our data suggests that the reduction of the cardiac Sigmar1 results in decrease mitochondrial Ca2+ influx and promotes mitochondrial fission, followed by reduced ER-mitochondria proximity, exacerbating ET-1-induced cardiomyocyte injury.

Keywords:  Cardiac hypertrophy; Mitochondria; Sigma receptors

DOI:  https://doi.org/10.1016/j.jphs.2022.12.005
Cell Rep. 2023 Jan 25. pii: S2211-1247(23)00048-7. [Epub ahead of print]42(2): 112037

The selective autophagy adaptor p62/SQSTM1 forms phase condensates regulated by HSP27 that facilitate the clearance of damaged lysosomes via lysophagy.

Elizabeth R Gallagher, Erika L F Holzbaur.

  In response to lysosomal damage, cells engage several quality-control mechanisms, including the selective isolation and degradation of damaged lysosomes by lysophagy. Here, we report that the selective autophagy adaptor SQSTM1/p62 is recruited to damaged lysosomes in both HeLa cells and neurons and is required for lysophagic flux. The Phox and Bem1p (PB1) domain of p62 mediates oligomerization and is specifically required for lysophagy. Consistent with this observation, we find that p62 forms condensates on damaged lysosomes. These condensates are precisely tuned by the small heat shock protein HSP27, which is phosphorylated in response to lysosomal injury and maintains the liquidity of p62 condensates, facilitating autophagosome formation. Mutations in p62 have been identified in patients with amyotrophic lateral sclerosis (ALS); ALS-associated mutations in p62 impair lysophagy, suggesting that deficits in this pathway may contribute to neurodegeneration. Thus, p62 condensates regulated by HSP27 promote lysophagy by forming platforms for autophagosome biogenesis at damaged lysosomes.

Keywords:  ALS; CP: Cell biology; CP: Neuroscience; HSP27; autophagy; condensates; lysophagy; lysosome; neurodegeneration; neurons; p62/SQSTM1; phase separation

DOI:  https://doi.org/10.1016/j.celrep.2023.112037
Mitochondrion. 2023 Jan 20. pii: S1567-7249(23)00005-3. [Epub ahead of print]

Severe acute respiratory syndrome coronaviruses contributing to mitochondrial dysfunction: Implications for post-COVID complications.

Shama Prasada Kabekkodu, Sanjiban Chakrabarty, Pradyumna Jayaram, Sandeep Mallya, Kumarasamy Thangaraj, Keshav K Singh, Kapaettu Satyamoorthy.

  Mitochondria play a central role in oxidative phosphorylation (OXPHOS), bioenergetics linked with ATP production, fatty acids biosynthesis, calcium signaling, cell cycle regulation, apoptosis, and innate immune response. Severe acute respiratory syndrome-associated coronavirus (SARS-CoV) infection manipulates the host cellular machinery for its survival and replication in the host cell. The infectiaon causes perturbed the cellular metabolism that favours viral replication leading to mitochondrial dysfunction and chronic inflammation. By localizing to the mitochondria, SARS CoV proteins increase reactive oxygen species (ROS) levels, perturbation of Ca2+ signaling, changes in mtDNA copy number, mitochondrial membrane potential (MMP), mitochondrial mass, and induction of mitophagy. These proteins also influence the fusion and fission kinetics, size, structure, and distribution of mitochondria in the infected host cells. This results in compromised bioenergetics, altered metabolism, and innate immune signaling, and hence can be a key player in determining the outcome of SARS-CoV infection. SARS-CoV infection contributes to stress and activates apoptotic pathways. This review summarizes how mitochondrial function and dynamics are affected by SARS-CoV and how the mitochondria-SARS-CoV interaction benefits viral survival and growth by evading innate host immunity. We also highlight how the SARS-CoV-mediated mitochondrial dysfunction contributes to post-COVID complications. Besides, a discussion on targeting virus-mitochondria interactions as a therapeutic strategy is presented.

Keywords:  CoV; Mitochondria; Mitochondrial localization signal; ROS; SARS; Virus

DOI:  https://doi.org/10.1016/j.mito.2023.01.005
Nat Cell Biol. 2023 Jan 23.

Small heat shock proteins operate as molecular chaperones in the mitochondrial intermembrane space.

Elias Adriaenssens, Bob Asselbergh, Pablo Rivera-Mejías, Sven Bervoets, Leen Vendredy, Vicky De Winter, Katrien Spaas, Riet de Rycke, Gert van Isterdael, Francis Impens, Thomas Langer, Vincent Timmerman.

Mitochondria are complex organelles with different compartments, each harbouring their own protein quality control factors. While chaperones of the mitochondrial matrix are well characterized, it is poorly understood which chaperones protect the mitochondrial intermembrane space. Here we show that cytosolic small heat shock proteins are imported under basal conditions into the mitochondrial intermembrane space, where they operate as molecular chaperones. Protein misfolding in the mitochondrial intermembrane space leads to increased recruitment of small heat shock proteins. Depletion of small heat shock proteins leads to mitochondrial swelling and reduced respiration, while aggregation of aggregation-prone substrates is countered in their presence. Charcot-Marie-Tooth disease-causing mutations disturb the mitochondrial function of HSPB1, potentially linking previously observed mitochondrial dysfunction in Charcot-Marie-Tooth type 2F to its role in the mitochondrial intermembrane space. Our results reveal that small heat shock proteins form a chaperone system that operates in the mitochondrial intermembrane space.

DOI: https://doi.org/10.1038/s41556-022-01074-9
Nature. 2023 Jan 25.

Mitochondrial complexome reveals quality-control pathways of protein import.

Uwe Schulte, Fabian den Brave, Alexander Haupt, Arushi Gupta, Jiyao Song, Catrin S Müller, Jeannine Engelke, Swadha Mishra, Christoph Mårtensson, Lars Ellenrieder, Chantal Priesnitz, Sebastian P Straub, Kim Nguyen Doan, Bogusz Kulawiak, Wolfgang Bildl, Heike Rampelt, Nils Wiedemann, Nikolaus Pfanner, Bernd Fakler, Thomas Becker.

Mitochondria have crucial roles in cellular energetics, metabolism, signalling and quality control1-4. They contain around 1,000 different proteins that often assemble into complexes and supercomplexes such as respiratory complexes and preprotein translocases1,3-7. The composition of the mitochondrial proteome has been characterized1,3,5,6; however, the organization of mitochondrial proteins into stable and dynamic assemblies is poorly understood for major parts of the proteome1,4,7. Here we report quantitative mapping of mitochondrial protein assemblies using high-resolution complexome profiling of more than 90% of the yeast mitochondrial proteome, termed MitCOM. An analysis of the MitCOM dataset resolves >5,200 protein peaks with an average of six peaks per protein and demonstrates a notable complexity of mitochondrial protein assemblies with distinct appearance for respiration, metabolism, biogenesis, dynamics, regulation and redox processes. We detect interactors of the mitochondrial receptor for cytosolic ribosomes, of prohibitin scaffolds and of respiratory complexes. The identification of quality-control factors operating at the mitochondrial protein entry gate reveals pathways for preprotein ubiquitylation, deubiquitylation and degradation. Interactions between the peptidyl-tRNA hydrolase Pth2 and the entry gate led to the elucidation of a constitutive pathway for the removal of preproteins. The MitCOM dataset-which is accessible through an interactive profile viewer-is a comprehensive resource for the identification, organization and interaction of mitochondrial machineries and pathways.

DOI: https://doi.org/10.1038/s41586-022-05641-w
Free Radic Biol Med. 2023 Jan 20. pii: S0891-5849(23)00024-2. [Epub ahead of print]196 156-170

MORN4 protects cardiomyocytes against ischemic injury via MFN2-mediated mitochondrial dynamics and mitophagy.

Jinrun Zhou, Honghong Liu, Tianliang Zhang, Zhaohui Wang, Jiaojiao Zhang, Yao Lu, Zhiliang Li, Weihua Kong, Jing Zhao.

  The imbalance of mitochondrial fission and fusion dynamics causes ischemic cardiomyocyte apoptosis and heart injury by affecting mitophagy. Regulation of mitochondrial dynamics is an important therapeutic strategy for ischemic heart diseases. Considering the important roles of MORN motifs in heart diseases and chloroplast fission, we aimed to investigate the possible role of MORN repeat-containing protein 4 (MORN4) in the progression of myocardial infarction (MI), ischemic cardiomyocyte apoptosis, mitochondrial dynamics, and mitophagy. We found that in the MI mouse, MORN4 knockdown remarkably accelerated cardiac injury and fibrosis with deteriorating cardiac dysfunction. Sphingosylphosphorylcholine (SPC) alleviated ischemic cardiomyocyte apoptosis and heart injury through increased level of MORN4, indicating a vital function of MORN4 in heart with SPC used to clarify the molecular mechanisms underlying the functions of MORN4. Mechanistically, we found that MORN4 directly binds to MFN2 and promotes the phosphorylation of MFN2 S442 through Rho-associated protein kinase 2 (ROCK2), which mediates beneficial mitophagy induced by mitochondrial dynamics, while SPC promoted the binding of MORN4 and MFN2 and the process. Taken together, our data reveal a new perspective role of MORN4 in ischemic heart injury, and report that SPC could regulate myocardial mitochondrial homeostasis by activating the MORN4-MFN2 axis during the ischemic situation, this finding provides novel targets for improving myocardial ischemia tolerance and rescue of acute myocardial infarction.

Keywords:  MFN2; MORN4; Mitochondrial dynamics; Mitophagy; Myocardial infarction; Sphingosylphosphorylcholine

DOI:  https://doi.org/10.1016/j.freeradbiomed.2023.01.016
Redox Biol. 2023 Jan 18. pii: S2213-2317(23)00014-9. [Epub ahead of print]60 102613

Mitochondrial NAD kinase in health and disease.

Ren Zhang, Kezhong Zhang.

  Nicotinamide adenine dinucleotide phosphate (NADP), a co-enzyme and an electron carrier, plays crucial roles in numerous biological functions, including cellular metabolism and antioxidation. Because NADP is subcellular-membrane impermeable, eukaryotes compartmentalize NAD kinases (NADKs), the NADP biosynthetic enzymes. Mitochondria are fundamental organelles for energy production through oxidative phosphorylation. Ten years after the discovery of the mitochondrial NADK (known as MNADK or NADK2), a significant amount of knowledge has been obtained regarding its functions, mechanism of action, human biology, mouse models, crystal structures, and post-translation modifications. NADK2 phosphorylates NAD(H) to generate mitochondrial NADP(H). NADK2-deficient patients suffered from hyperlysinemia, elevated plasma C10:2-carnitine (due to the inactivity of relevant NADP-dependent enzymes), and neuronal development defects. Nadk2-deficient mice recapitulate key features of NADK2-deficient patients, including metabolic and neuronal abnormalities. Crystal structures of human NADK2 show a dimer, with the NADP+-binding site located at the dimer interface. NADK2 activity is highly regulated by post-translational modifications, including S188 phosphorylation, K76 and K304 acetylation, and C193 S-nitrosylation; mutations in each site affect NADK2 activity and function. In mice, hepatic Nadk2 functions as a major metabolic regulator upon increased energy demands by regulating sirtuin 3 activity and fatty acid oxidation. Hopefully, future research on NADK2 will not only elucidate its functional roles in health and disease but will also pave the way for novel therapeutics for both rare and common diseases, including NADK2 deficiency and metabolic syndrome.

Keywords:  Antioxidation; MNADK; Mitochondria; NAD; NADK; NADK2; NADP

DOI:  https://doi.org/10.1016/j.redox.2023.102613
PLoS Genet. 2023 Jan 25. 19(1): e1010610

Mitochondrial remodelling is essential for female germ cell differentiation and survival.

Vernon Leander Monteiro, Darya Safavian, Deepika Vasudevan, Thomas Ryan Hurd.

Stem cells often possess immature mitochondria with few inner membrane invaginations, which increase as stem cells differentiate. Despite this being a conserved feature across many stem cell types in numerous organisms, how and why mitochondria undergo such remodelling during stem cell differentiation has remained unclear. Here, using Drosophila germline stem cells (GSCs), we show that Complex V drives mitochondrial remodelling during the early stages of GSC differentiation, prior to terminal differentiation. This endows germline mitochondria with the capacity to generate large amounts of ATP required for later egg growth and development. Interestingly, impairing mitochondrial remodelling prior to terminal differentiation results in endoplasmic reticulum (ER) lipid bilayer stress, Protein kinase R-like ER kinase (PERK)-mediated activation of the Integrated Stress Response (ISR) and germ cell death. Taken together, our data suggest that mitochondrial remodelling is an essential and tightly integrated aspect of stem cell differentiation. This work sheds light on the potential impact of mitochondrial dysfunction on stem and germ cell function, highlighting ER lipid bilayer stress as a potential major driver of phenotypes caused by mitochondrial dysfunction.

DOI: https://doi.org/10.1371/journal.pgen.1010610
Shock. 2023 Jan 23.

Nucleolin protects cardiomyocytes by upregulating PGC-1α and promoting mitochondrial biogenesis in LPS-induced myocardial injury.

Leijing Yin, Yuting Tang, Zhengyang Luo, Ludong Yuan, Xiaofang Lin, Shuxin Wang, Pengfei Liang, Bimei Jiang.

BACKGROUND: LPS-induced myocardial injury was characterized by frequent mitochondrial dysfunction. Our previous studies found that nucleolin played important protective roles in myocardial ischemia-reperfusion injury. Recently, it has been found that nucleolin has a protective effect on LPS-induced myocardial injury in vivo. However, the exact underlying mechanisms that how nucleolin protects myocardium against the LPS-induced myocardial injury remains unclear.
OBJECTIVE: To investigate the protective role of nucleolin in LPS-induced myocardial injury from the aspect of mitochondrial biogenesis.
METHODS: The cardiac-specific nucleolin-knockout (NCL-/-) or NCLf/f mice were injected with lipopolysaccride (LPS) (10 mg/kg) to induce LPS-induced myocardial injury. The supernatant generated after LPS stimulation of macrophages was used as the conditioned medium to stimulate H9C2 and established the injured cell model. Analysis of mRNA stability, RNA Binding Protein Immunoprecipitation Assay (RIP), and luciferase reporter assay were performed to detect the mechanism by which nucleolin regulated the expression of PGC-1α.
RESULTS: The expression of nucleolin and PGC-1α were elevated in cardiac tissue and cardiomyocytes during LPS-induced myocardial injury. The cardiac-specific nucleolin-knockout decreased PGC-1α expression, inhibited mitochondrial biogenesis, increased cardiomyocytes death during LPS-induced myocardial injury in vitro and in vivo. In contrast, the overexpression of nucleolin could improve mitochondrial biogenesis in H9C2 cells. Moreover, the analysis of mRNA stability, and luciferase reporter assay revealed that the interaction between nucleolin and PGC-1α significantly promoted the stability of PGC-1α mRNA, thereby up-regulating the expression of PGC-1α and exerting a cardioprotective effect. In addition, the activation of PGC-1α diminished the detrimental effects of nucleolin-knockdown on mitochondrial biogenesis in vitro and in vivo.
CONCLUSION: Nucleolin up-regulated the gene expression of PGC-1α by directly binding to the 5'-UTR of PGC-1α mRNA and increasing its mRNA stabilities, and then promoted mitochondrial biogenesis, played protective effect on cardiomyocytes during LPS-induced myocardial injury. Taken together, all these data showed that nucleolin activated PGC-1α to rescue cardiomyocytes from LPS-induced myocardial injury insult, suggesting that the cardioprotective role of nucleolin might be a promising prospect for clinical treatment of patients with endotoxemia.

DOI: https://doi.org/10.1097/SHK.0000000000002084