bims-mikwok 2021-04-04 papers

bims-mikwok

Biomed News

on Mitochondrial quality control

Issue of 2021‒04‒04
twenty-one papers selected by
Avinash N. Mukkala, University of Toronto

Opa1 relies on cristae preservation and ATP synthase to curtail reactive oxygen species accumulation in mitochondria.
Mitochondrial quality control: from molecule to organelle.
ATG4 family proteins drive phagophore growth independently of the LC3/GABARAP lipidation system.
Selective packaging of mitochondrial proteins into extracellular vesicles prevents the release of mitochondrial DAMPs.
Cell Death and Inflammation: The Role of Mitochondria in Health and Disease.
Mitochondria transplantation protects traumatic brain injury via promoting neuronal survival and astrocytic BDNF.
Unraveling the Link Between Mitochondrial Dynamics and Neuroinflammation.
NIX Mediates Mitophagy in Spinal Cord Injury in Rats by Interacting with LC3.
Nicotinamide Treatment Facilitates Mitochondrial Fission through Drp1 Activation Mediated by SIRT1-Induced Changes in Cellular Levels of cAMP and Ca2.
The Phosphorylation Status of Drp1-Ser637 by PKA in Mitochondrial Fission Modulates Mitophagy via PINK1/Parkin to Exert Multipolar Spindles Assembly during Mitosis.
Impaired F1Fo-ATP-Synthase Dimerization Leads to the Induction of Cyclophilin D-Mediated Autophagy-Dependent Cell Death and Accelerated Aging.
Genome-wide RNAi screen for regulators of UPRmt in Caenorhabditis elegans mutants with defects in mitochondrial fusion.
KRT8 (keratin 8) attenuates necrotic cell death by facilitating mitochondrial fission-mediated mitophagy through interaction with PLEC (plectin).
Dexmedetomidine ameliorates endotoxin-induced acute lung injury in vivo and in vitro by preserving mitochondrial dynamic equilibrium through the HIF-1a/HO-1 signaling pathway.
Stimulation of mTOR-independent autophagy and mitophagy by rilmenidine exacerbates the phenotype of transgenic TDP-43 mice.
Mitochondrial Consequences of Organ Preservation Techniques during Liver Transplantation.
Mitochondrial matrix-localized p53 participates in degradation of mitochondrial RNAs.
Mitochondrial Mistranslation in Brain Provokes a Metabolic Response Which Mitigates the Age-Associated Decline in Mitochondrial Gene Expression.
Role of Mitochondria in Viral Infections.
Endoplasmic Reticulum & Mitochondrial Calcium homeostasis: The Interplay with Viruses.
Mitochondrial Transfer in Cancer: A Comprehensive Review.

Redox Biol. 2021 Mar 19. pii: S2213-2317(21)00092-6. [Epub ahead of print]41 101944

Opa1 relies on cristae preservation and ATP synthase to curtail reactive oxygen species accumulation in mitochondria.

Rubén Quintana-Cabrera, Israel Manjarrés-Raza, Carlos Vicente-Gutiérrez, Mauro Corrado, Juan P Bolaños, Luca Scorrano.

  Reactive oxygen species (ROS) are a common product of active mitochondrial respiration carried in mitochondrial cristae, but whether cristae shape influences ROS levels is unclear. Here we report that the mitochondrial fusion and cristae shape protein Opa1 requires mitochondrial ATP synthase oligomers to reduce ROS accumulation. In cells fueled with galactose to force ATP production by mitochondria, cristae are enlarged, ATP synthase oligomers destabilized, and ROS accumulate. Opa1 prevents both cristae remodeling and ROS generation, without impinging on levels of mitochondrial antioxidant defense enzymes that are unaffected by Opa1 overexpression. Genetic and pharmacologic experiments indicate that Opa1 requires ATP synthase oligomerization and activity to reduce ROS levels upon a blockage of the electron transport chain. Our results indicate that the converging effect of Opa1 and mitochondrial ATP synthase on mitochondrial ultrastructure regulate ROS abundance to sustain cell viability.

Keywords:  Bioenergetics; F(1)F(O)-ATP synthase; Mitochondrial cristae; Opa1; ROS; Ultrastructure

DOI:  https://doi.org/10.1016/j.redox.2021.101944
Cell Mol Life Sci. 2021 Mar 29.

Mitochondrial quality control: from molecule to organelle.

Alba Roca-Portoles, Stephen W G Tait.

  Mitochondria are organelles central to myriad cellular processes. To maintain mitochondrial health, various processes co-operate at both the molecular and organelle level. At the molecular level, mitochondria can sense imbalances in their homeostasis and adapt to these by signaling to the nucleus. This mito-nuclear communication leads to the expression of nuclear stress response genes. Upon external stimuli, mitochondria can also alter their morphology accordingly, by inducing fission or fusion. In an extreme situation, mitochondria are degraded by mitophagy. Adequate function and regulation of these mitochondrial quality control pathways are crucial for cellular homeostasis. As we discuss, alterations in these processes have been linked to several pathologies including neurodegenerative diseases and cancer.

Keywords:  ISR; Mitochondrial diseases; Mitochondrial dysfunction; Mitochondrial fission; Mitochondrial fusion; Mitophagy; PINK1; Parkin; UPRmt

DOI:  https://doi.org/10.1007/s00018-021-03775-0
Mol Cell. 2021 Mar 25. pii: S1097-2765(21)00169-6. [Epub ahead of print]

ATG4 family proteins drive phagophore growth independently of the LC3/GABARAP lipidation system.

Thanh Ngoc Nguyen, Benjamin Scott Padman, Susanne Zellner, Grace Khuu, Louise Uoselis, Wai Kit Lam, Marvin Skulsuppaisarn, Runa S J Lindblom, Emily M Watts, Christian Behrends, Michael Lazarou.

  The sequestration of damaged mitochondria within double-membrane structures termed autophagosomes is a key step of PINK1/Parkin mitophagy. The ATG4 family of proteases are thought to regulate autophagosome formation exclusively by processing the ubiquitin-like ATG8 family (LC3/GABARAPs). We discover that human ATG4s promote autophagosome formation independently of their protease activity and of ATG8 family processing. ATG4 proximity networks reveal a role for ATG4s and their proximity partners, including the immune-disease protein LRBA, in ATG9A vesicle trafficking to mitochondria. Artificial intelligence-directed 3D electron microscopy of phagophores shows that ATG4s promote phagophore-ER contacts during the lipid-transfer phase of autophagosome formation. We also show that ATG8 removal during autophagosome maturation does not depend on ATG4 activity. Instead, ATG4s can disassemble ATG8-protein conjugates, revealing a role for ATG4s as deubiquitinating-like enzymes. These findings establish non-canonical roles of the ATG4 family beyond the ATG8 lipidation axis and provide an AI-driven framework for rapid 3D electron microscopy.

Keywords:  ATG4; ATG9a; FIB-SEM; LRBA; PINK1; Parkin; autophagosome; autophagy; mitochondria; mitophagy

DOI:  https://doi.org/10.1016/j.molcel.2021.03.001
Nat Commun. 2021 Mar 30. 12(1): 1971

Selective packaging of mitochondrial proteins into extracellular vesicles prevents the release of mitochondrial DAMPs.

Kiran Todkar, Lilia Chikhi, Véronique Desjardins, Firas El-Mortada, Geneviève Pépin, Marc Germain.

Most cells constitutively secrete mitochondrial DNA and proteins in extracellular vesicles (EVs). While EVs are small vesicles that transfer material between cells, Mitochondria-Derived Vesicles (MDVs) carry material specifically between mitochondria and other organelles. Mitochondrial content can enhance inflammation under pro-inflammatory conditions, though its role in the absence of inflammation remains elusive. Here, we demonstrate that cells actively prevent the packaging of pro-inflammatory, oxidized mitochondrial proteins that would act as damage-associated molecular patterns (DAMPs) into EVs. Importantly, we find that the distinction between material to be included into EVs and damaged mitochondrial content to be excluded is dependent on selective targeting to one of two distinct MDV pathways. We show that Optic Atrophy 1 (OPA1) and sorting nexin 9 (Snx9)-dependent MDVs are required to target mitochondrial proteins to EVs, while the Parkinson's disease-related protein Parkin blocks this process by directing damaged mitochondrial content to lysosomes. Our results provide insight into the interplay between mitochondrial quality control mechanisms and mitochondria-driven immune responses.

DOI: https://doi.org/10.1038/s41467-021-21984-w
Cells. 2021 Mar 03. pii: 537. [Epub ahead of print]10(3):

Cell Death and Inflammation: The Role of Mitochondria in Health and Disease.

Anna Picca, Riccardo Calvani, Hélio José Coelho-Junior, Emanuele Marzetti.

  Mitochondria serve as a hub for a multitude of vital cellular processes. To ensure an efficient deployment of mitochondrial tasks, organelle homeostasis needs to be preserved. Mitochondrial quality control (MQC) mechanisms (i.e., mitochondrial dynamics, biogenesis, proteostasis, and autophagy) are in place to safeguard organelle integrity and functionality. Defective MQC has been reported in several conditions characterized by chronic low-grade inflammation. In this context, the displacement of mitochondrial components, including mitochondrial DNA (mtDNA), into the extracellular compartment is a possible factor eliciting an innate immune response. The presence of bacterial-like CpG islands in mtDNA makes this molecule recognized as a damaged-associated molecular pattern by the innate immune system. Following cell death-triggering stressors, mtDNA can be released from the cell and ignite inflammation via several pathways. Crosstalk between autophagy and apoptosis has emerged as a pivotal factor for the regulation of mtDNA release, cell's fate, and inflammation. The repression of mtDNA-mediated interferon production, a powerful driver of immunological cell death, is also regulated by autophagy-apoptosis crosstalk. Interferon production during mtDNA-mediated inflammation may be exploited for the elimination of dying cells and their conversion into elements driving anti-tumor immunity.

Keywords:  apoptosis; damage-associated molecular patterns (DAMPs); immunogenic cell death; innate immunity; mitochondrial dynamics; mitochondrial dysfunction; mitochondrial quality control (MQC); mitophagy; oxidative stress; reactive oxygen species (ROS)

DOI:  https://doi.org/10.3390/cells10030537
Transl Res. 2021 Mar 30. pii: S1931-5244(21)00080-3. [Epub ahead of print]

Mitochondria transplantation protects traumatic brain injury via promoting neuronal survival and astrocytic BDNF.

Jiqian Zhao, Dujie Qu, Zihan Xi, Yu Huan, Kun Zhang, Caiyong Yu, Dingding Yang, Junjun Kang, Wei Lin, Shengxi Wu, Yazhou Wang.

  Traumatic brain injury (TBI) is one of the leading causes of disability and paralysis around the world. Secondary injury, characterized by progressive neuronal loss and astrogliosis, plays important roles in the post-TBI cognitive impairment and mood disorder. Unfortunately, there still lacks effective treatments, particularly surgery interferences for it. Recent findings of intercellular mitochondria transfer implies a potential therapeutic value of mitochondria transplantation for TBI, which has not been tested yet. In the present study, we demonstrated a quick dysfunction of mitochondria, up-regulation of Tom20 in the injured cortex and subsequent cognitive and mood impairment. Our data demonstrated that mitochondria derived from allogeneic liver or autogeneic muscle stimulated similar microglial activation in brain parenchyma. In vitro experiments showed that exogenous mitochondria could be easily internalized by neurons, astrocytes and microglia, except for oligodendrocytes. Mitochondria transplantation effectively rescued neuronal apoptosis, restored the expression of Tom20 and the phosphorylation of JNK. Further analysis revealed that mitochondria transplantation in injured cortex induced a significant up-regulation of BDNF in reactive astrocytes, improved animals' spatial memory and alleviated anxiety. In together, our data indicate that mitochondria transplantation may has the potential of clinical translation for TBI treatment, in combination with surgery.

Keywords:  Astrocyte; Mitochondria; Secondary injury; Transplantation; Traumatic brain injury

DOI:  https://doi.org/10.1016/j.trsl.2021.03.017
Front Immunol. 2021 ;12 624919

Unraveling the Link Between Mitochondrial Dynamics and Neuroinflammation.

Lilian Gomes de Oliveira, Yan de Souza Angelo, Antonio H Iglesias, Jean Pierre Schatzmann Peron.

  Neuroinflammatory and neurodegenerative diseases are a major public health problem worldwide, especially with the increase of life-expectancy observed during the last decades. For many of these diseases, we still lack a full understanding of their etiology and pathophysiology. Nonetheless their association with mitochondrial dysfunction highlights this organelle as an important player during CNS homeostasis and disease. Markers of Parkinson (PD) and Alzheimer (AD) diseases are able to induce innate immune pathways induced by alterations in mitochondrial Ca2+ homeostasis leading to neuroinflammation. Additionally, exacerbated type I IFN responses triggered by mitochondrial DNA (mtDNA), failures in mitophagy, ER-mitochondria communication and mtROS production promote neurodegeneration. On the other hand, regulation of mitochondrial dynamics is essential for CNS health maintenance and leading to the induction of IL-10 and reduction of TNF-α secretion, increased cell viability and diminished cell injury in addition to reduced oxidative stress. Thus, although previously solely seen as power suppliers to organelles and molecular processes, it is now well established that mitochondria have many other important roles, including during immune responses. Here, we discuss the importance of these mitochondrial dynamics during neuroinflammation, and how they correlate either with the amelioration or worsening of CNS disease.

Keywords:  Alzheimer disease; Parkinson disease; mitochondria; multiple sclerosis; neurodegenerative diseases; neuroinflammation

DOI:  https://doi.org/10.3389/fimmu.2021.624919
Cell Mol Neurobiol. 2021 Mar 29.

NIX Mediates Mitophagy in Spinal Cord Injury in Rats by Interacting with LC3.

Piming Nie, Honggang Wang, Datang Yu, Hongchen Wu, Bing Ni, Jiming Kong, Zhengfeng Zhang.

  Excessive mitophagy plays a role in neuronal death in spinal cord injury (SCI), its molecular regulation remains largely unknown. The present study aims to determine the role of NIX, a member of a unique subfamily of death-inducing mitochondrial proteins, in the regulation of mitophagy in SCI. Here we show that NIX is highly upregulated in SCI and hypoxia, and localized to mitochondria. The mitochondria-bound NIX interacts with autophagosome-localized LC3 (Microtubule-associated protein 1 light chain 3) to form a mitochondria-NIX-LC3-autophagosome complex, resulting in excessive mitophagy in SCI. Downregulation of NIX by RNA interference restores the function of mitochondria in spinal cord neurons under hypoxia. Importantly, inhibition of NIX improves recovery of locomotor function in rats after SCI. The present study demonstrates that NIX interacts with LC3 to activate excessive mitophagy in SCI. Inhibition of NIX is therefore likely a neuroprotective strategy.

Keywords:  Hypoxia; LC3; Mitophagy; NIX; Spinal cord injury

DOI:  https://doi.org/10.1007/s10571-021-01082-7
Cells. 2021 Mar 10. pii: 612. [Epub ahead of print]10(3):

Nicotinamide Treatment Facilitates Mitochondrial Fission through Drp1 Activation Mediated by SIRT1-Induced Changes in Cellular Levels of cAMP and Ca2.

Seon Beom Song, Jin Sung Park, So Young Jang, Eun Seong Hwang.

  Mitochondrial autophagy (or mitophagy) is essential for mitochondrial quality control, which is critical for cellular and organismal health by attenuating reactive oxygen species generation and maintaining bioenergy homeostasis. Previously, we showed that mitophagy is activated in human cells through SIRT1 activation upon treatment of nicotinamide (NAM). Further, mitochondria are maintained as short fragments in the treated cells. In the current study, molecular pathways for NAM-induced mitochondrial fragmentation were sought. NAM treatment induced mitochondrial fission, at least in part by activating dynamin-1-like protein (Drp1), and this was through attenuation of the inhibitory phosphorylation at serine 637 (S637) of Drp1. This Drp1 hypo-phosphorylation was attributed to SIRT1-mediated activation of AMP-activated protein kinase (AMPK), which in turn induced a decrease in cellular levels of cyclic AMP (cAMP) and protein kinase A (PKA) activity, a kinase targeting S637 of Drp1. Furthermore, in NAM-treated cells, cytosolic Ca2+ was highly maintained; and, as a consequence, activity of calcineurin, a Drp1-dephosphorylating phosphatase, is expected to be elevated. These results suggest that NAD+-mediated SIRT1 activation facilitates mitochondrial fission through activation of Drp1 by suppressing its phosphorylation and accelerating its dephosphorylation. Additionally, it is suggested that there is a cycle of mitochondrial fragmentation and cytosolic Ca2+-mediated Drp1 dephosphorylation that may drive sustained mitochondrial fragmentation.

Keywords:  AMPK; Drp1; SIRT1; calcineurin; mitochondrial fragmentation; nicotinamide

DOI:  https://doi.org/10.3390/cells10030612
Biomolecules. 2021 Mar 13. pii: 424. [Epub ahead of print]11(3):

The Phosphorylation Status of Drp1-Ser637 by PKA in Mitochondrial Fission Modulates Mitophagy via PINK1/Parkin to Exert Multipolar Spindles Assembly during Mitosis.

Huey-Jiun Ko, Cheng-Yu Tsai, Shean-Jaw Chiou, Yun-Ling Lai, Chi-Huei Wang, Jiin-Tsuey Cheng, Tsung-Hsien Chuang, Chi-Ying F Huang, Aij-Lie Kwan, Joon-Khim Loh, Yi-Ren Hong.

  Mitochondrial fission and fusion cycles are integrated with cell cycle progression. Here we first re-visited how mitochondrial ETC inhibition disturbed mitosis progression, resulting in multipolar spindles formation in HeLa cells. Inhibitors of ETC complex I (rotenone, ROT) and complex III (antimycin A, AA) decreased the phosphorylation of Plk1 T210 and Aurora A T288 in the mitotic phase (M-phase), especially ROT, affecting the dynamic phosphorylation status of fission protein dynamin-related protein 1 (Drp1) and the Ser637/Ser616 ratio. We then tested whether specific Drp1 inhibitors, Mdivi-1 or Dynasore, affected the dynamic phosphorylation status of Drp1. Similar to the effects of ROT and AA, our results showed that Mdivi-1 but not Dynasore influenced the dynamic phosphorylation status of Ser637 and Ser616 in Drp1, which converged with mitotic kinases (Cdk1, Plk1, Aurora A) and centrosome-associated proteins to significantly accelerate mitotic defects. Moreover, our data also indicated that evoking mito-Drp1-Ser637 by protein kinase A (PKA) rather than Drp1-Ser616 by Cdk1/Cyclin B resulted in mitochondrial fission via the PINK1/Parkin pathway to promote more efficient mitophagy and simultaneously caused multipolar spindles. Collectively, this study is the first to uncover that mito-Drp1-Ser637 by PKA, but not Drp1-Ser616, drives mitophagy to exert multipolar spindles formation during M-phase.

Keywords:  Drp1; PKA; centrosomes; mitochondria; mitophagy; multipolar spindles; phosphorylation

DOI:  https://doi.org/10.3390/biom11030424
Cells. 2021 Mar 30. pii: 757. [Epub ahead of print]10(4):

Impaired F1Fo-ATP-Synthase Dimerization Leads to the Induction of Cyclophilin D-Mediated Autophagy-Dependent Cell Death and Accelerated Aging.

Verena Warnsmann, Lisa-Marie Marschall, Heinz D Osiewacz.

  Mitochondrial F1Fo-ATP-synthase dimers play a critical role in shaping and maintenance of mitochondrial ultrastructure. Previous studies have revealed that ablation of the F1Fo-ATP-synthase assembly factor PaATPE of the ascomycete Podospora anserina strongly affects cristae formation, increases hydrogen peroxide levels, impairs mitochondrial function and leads to premature cell death. In the present study, we investigated the underlying mechanistic basis. Compared to the wild type, we observed a slight increase in non-selective and a pronounced increase in mitophagy, the selective vacuolar degradation of mitochondria. This effect depends on the availability of functional cyclophilin D (PaCYPD), the regulator of the mitochondrial permeability transition pore (mPTP). Simultaneous deletion of PaAtpe and PaAtg1, encoding a key component of the autophagy machinery or of PaCypD, led to a reduction of mitophagy and a partial restoration of the wild-type specific lifespan. The same effect was observed in the PaAtpe deletion strain after inhibition of PaCYPD by its specific inhibitor, cyclosporin A. Overall, our data identify autophagy-dependent cell death (ADCD) as part of the cellular response to impaired F1Fo-ATP-synthase dimerization, and emphasize the crucial role of functional mitochondria in aging.

Keywords:  ADCD; F1Fo-ATP-synthase; Podospora anserina; mPTP; mitophagy

DOI:  https://doi.org/10.3390/cells10040757
G3 (Bethesda). 2021 Mar 30. pii: jkab095. [Epub ahead of print]

Genome-wide RNAi screen for regulators of UPRmt in Caenorhabditis elegans mutants with defects in mitochondrial fusion.

Simon Haeussler, Assa Yeroslaviz, Stéphane G Rolland, Sebastian Luehr, Eric J Lambie, Barbara Conradt.

  Mitochondrial dynamics plays an important role in mitochondrial quality control and the adaptation of metabolic activity in response to environmental changes. The disruption of mitochondrial dynamics has detrimental consequences for mitochondrial and cellular homeostasis and leads to the activation of the mitochondrial unfolded protein response (UPRmt), a quality control mechanism that adjusts cellular metabolism and restores homeostasis. To identify genes involved in the induction of UPRmt in response to a block in mitochondrial fusion, we performed a genome-wide RNAi screen in Caenorhabditis elegans mutants lacking the gene fzo-1, which encodes the ortholog of mammalian Mitofusin, and identified 299 suppressors and 86 enhancers. Approximately 90% of these 385 genes are conserved in humans, and one third of the conserved genes have been implicated in human disease. Furthermore, many have roles in developmental processes, which suggests that mitochondrial function and the response to stress are defined during development and maintained throughout life. Our dataset primarily contains mitochondrial enhancers and non-mitochondrial suppressors of UPRmt, indicating that the maintenance of mitochondrial homeostasis has evolved as a critical cellular function, which, when disrupted, can be compensated for by many different cellular processes. Analysis of the subsets 'non-mitochondrial enhancers' and 'mitochondrial suppressors' suggests that organellar contact sites, especially between the ER and mitochondria, are of importance for mitochondrial homeostasis. In addition, we identified several genes involved in IP3 signaling that modulate UPRmt in fzo-1 mutants and found a potential link between pre-mRNA splicing and UPRmt activation.

Keywords:  IP3 signaling; Mitoguardin; fzo-1; mitochondrial dynamics; mitochondrial unfolded protein response

DOI:  https://doi.org/10.1093/g3journal/jkab095
Autophagy. 2021 Mar 30. 1-18

KRT8 (keratin 8) attenuates necrotic cell death by facilitating mitochondrial fission-mediated mitophagy through interaction with PLEC (plectin).

Ahruem Baek, Sumin Son, Yu Mi Baek, Dong-Eun Kim.

  Dysregulation of mitochondrial homeostasis and accumulation of damaged mitochondria cause degenerative diseases such as age-related macular degeneration (AMD). We studied the effects of the intermediate cytofilament KRT8 (keratin 8) on mitochondrial homeostasis in relation to the morphology and function of mitochondria in retinal pigment epithelial cells under oxidative stress. When the mitochondria were damaged owing to oxidative stress, the damaged mitochondria were readily disposed of via mitophagy following mitochondrial fission. During this process, KRT8 was found to physically interact with the mitochondria through PLEC (plectin) and facilitate the mitochondrial fission-mediated mitophagy. However, the association between PLEC-anchoring mitochondria and KRT8 was dwindled by KRT8 phosphorylation under oxidative stress. The efficient KRT8-facilitated mitophagy flux suppressed the accumulation of damaged mitochondria and consequently diminished necrotic cell death under oxidative stress. Thus, by facilitating mitophagy, KRT8 protects RPE cells against necrotic cell death due to oxidative stress.

Keywords:  Age-related macular degeneration (AMD); Plectin (PLEC); autophagy; keratin 8 (KRT8); mitochondrial fission; mitophagy; necrosis

DOI:  https://doi.org/10.1080/15548627.2021.1897962
Redox Biol. 2021 Mar 21. pii: S2213-2317(21)00102-6. [Epub ahead of print]41 101954

Dexmedetomidine ameliorates endotoxin-induced acute lung injury in vivo and in vitro by preserving mitochondrial dynamic equilibrium through the HIF-1a/HO-1 signaling pathway.

Jia Shi, Tianxi Yu, Kai Song, Shihan Du, Simeng He, Xinxin Hu, Xiangyun Li, Haibo Li, Shuan Dong, Yuan Zhang, Zilei Xie, Cui Li, Jianbo Yu.

  Increasing lines of evidence identified that dexmedetomidine (DEX) exerted protective effects against sepsis-stimulated acute lung injury via anti-inflammation, anti-oxidation and anti-apoptosis. However, the mechanisms remain unclear. Herein, we investigated whether DEX afforded lung protection by regulating the process of mitochondrial dynamics through the HIF-1a/HO-1 pathway in vivo and in vitro. Using C57BL/6J mice exposed to lipopolysaccharide, it was initially observed that preemptive administration of DEX (50μg/kg) alleviated lung pathologic injury, reduced oxidative stress indices (OSI), improved mitochondrial dysfunction, upregulated the expression of HIF-1α and HO-1, accompanied by shifting the dynamic course of mitochondria into fusion. Moreover, HO-1-knockout mice or HO-1 siRNA transfected NR8383 cells were pretreated with HIF-1α stabilizer DMOG and DEX to validate the effect of HIF-1a/HO-1 pathway on DEX-mediated mitochondrial dynamics in a model of endotoxin-induced lung injury. We found that pretreatment with DEX and DMOG distinctly relieved lung injury, decreased the levels of mitochondrial ROS and mtDNA, reduced OSI, increased nuclear accumulation of HIF-1a and HO-1 protein in wild type mice but not HO-1 KO mice. Similar observations were recapitulated in NC siRNA transfected NR8383 cells after LPS stimulation but not HO-1 siRNA transfected cells. Concertedly, DEX reversed the impaired mitochondrial morphology in LPS stimulated-wild type mice or NC siRNA transfected NR8383 cells, upregulated the expression of mitochondrial fusion protein, while downregulated the expression of fission protein in HIF-1a/HO-1 dependent pathway. Altogether, our data both in vivo and in vitro certified that DEX treatment ameliorated endotoxin-induced acute lung injury by preserving the dynamic equilibrium of mitochondrial fusion/fission through the regulation of HIF-1a/HO-1 signaling pathway.

Keywords:  Acute lung injury; Dexmedetomidine; Endotoxin; Heme oxygenase-1; Hypoxia-inducible factor 1; Mitochondrial dynamics

DOI:  https://doi.org/10.1016/j.redox.2021.101954
Neurobiol Dis. 2021 Mar 30. pii: S0969-9961(21)00108-X. [Epub ahead of print] 105359

Stimulation of mTOR-independent autophagy and mitophagy by rilmenidine exacerbates the phenotype of transgenic TDP-43 mice.

Nirma D Perera, Doris Tomas, Nayomi Wanniarachchillage, Brittany Cuic, Sophia J Luikinga, Valeria Rytova, Bradley J Turner.

  Autophagy, which mediates delivery of cytoplasmic substrates to the lysosome for degradation, is essential for maintaining proper cell homeostasis in physiology, ageing and disease. There is increasing evidence that autophagy is defective in neurodegenerative disorders, including motor neurons affected in amyotrophic lateral sclerosis (ALS). Restoring impaired autophagy in motor neurons may therefore represent a rational approach for ALS. Here, we demonstrate autophagy impairment in spinal cords of mice expressing mutant TDP-43Q331K or co-expressing TDP-43WTxQ331K transgenes. The clinically approved anti-hypertensive drug rilmenidine was used to stimulate mTOR-independent autophagy in double transgenic TDP-43WTxQ331K mice to alleviate impaired autophagy. Although rilmenidine treatment induced robust autophagy in spinal cords, this exacerbated the phenotype of TDP-43WTxQ331K mice shown by truncated lifespan, accelerated motor neuron loss and pronounced nuclear TDP-43 clearance. Importantly, rilmenidine significantly promoted mitophagy in spinal cords TDP-43WTxQ331K mice, evidenced by reduced mitochondrial markers and load in spinal motor neurons. These results suggest that autophagy induction accelerates the phenotype of this TDP-43 mouse model of ALS, most likely through excessive mitochondrial clearance in motor neurons. These findings also emphasise the importance of balancing autophagy stimulation with the potential negative consequences of hyperactive mitophagy in ALS and other neurodegenerative diseases.

Keywords:  ALS; Autophagy; Motor neuron; Rilmenidine; TDP-43

DOI:  https://doi.org/10.1016/j.nbd.2021.105359
Int J Mol Sci. 2021 Mar 10. pii: 2816. [Epub ahead of print]22(6):

Mitochondrial Consequences of Organ Preservation Techniques during Liver Transplantation.

Tamara Horváth, Dávid Kurszán Jász, Bálint Baráth, Marietta Zita Poles, Mihály Boros, Petra Hartmann.

  Allograft ischemia during liver transplantation (LT) adversely affects the function of mitochondria, resulting in impairment of oxidative phosphorylation and compromised post-transplant recovery of the affected organ. Several preservation methods have been developed to improve donor organ quality; however, their effects on mitochondrial functions have not yet been compared. This study aimed to summarize the available data on mitochondrial effects of graft preservation methods in preclinical models of LT. Furthermore, a network meta-analysis was conducted to determine if any of these treatments provide a superior benefit, suggesting that they might be used on humans. A systematic search was conducted using electronic databases (EMBASE, MEDLINE (via PubMed), the Cochrane Central Register of Controlled Trials (CENTRAL) and Web of Science) for controlled animal studies using preservation methods for LT. The ATP content of the graft was the primary outcome, as this is an indicator overall mitochondrial function. Secondary outcomes were the respiratory activity of mitochondrial complexes, cytochrome c and aspartate aminotransferase (ALT) release. Both a random-effects model and the SYRCLE risk of bias analysis for animal studies were used. After a comprehensive search of the databases, 25 studies were enrolled in the analysis. Treatments that had the most significant protective effect on ATP content included hypothermic and subnormothermic machine perfusion (HMP and SNMP) (MD = -1.0, 95% CI: (-2.3, 0.3) and MD = -1.1, 95% CI: (-3.2, 1.02)), while the effects of warm ischemia (WI) without cold storage (WI) and normothermic machine perfusion (NMP) were less pronounced (MD = -1.8, 95% CI: (-2.9, -0.7) and MD = -2.1 MD; CI: (-4.6; 0.4)). The subgroup of static cold storage (SCS) with shorter preservation time (< 12 h) yielded better results than SCS ≥ 12 h, NMP and WI, in terms of ATP preservation and the respiratory capacity of complexes. HMP and SNMP stand out in terms of mitochondrial protection when compared to other treatments for LT in animals. The shorter storage time at lower temperatures, together with the dynamic preservation, provided superior protection for the grafts in terms of mitochondrial function. Additional clinical studies on human patients including marginal donors and longer ischemia times are needed to confirm any superiority of preservation methods with respect to mitochondrial function.

Keywords:  animal studies; graft preservation; liver transplantation; meta-analysis; mitochondrial functions

DOI:  https://doi.org/10.3390/ijms22062816
Mitochondrion. 2021 Mar 25. pii: S1567-7249(21)00039-8. [Epub ahead of print]

Mitochondrial matrix-localized p53 participates in degradation of mitochondrial RNAs.

Yael Friedman, Amnon Hizi, Dror Avni, Mary Bakhanashvili.

  Mitochondrial RNA degradation plays an important role in maintenance of the mitochondria genetic integrity. Mitochondrial localization of p53 was observed in non-stressed and stressed cells. p53, as an RNA-binding protein, exerts 3'→5' exoribonuclease activity. The data suggest that in non-stressed cells, mitochondrial matrix-localized p53, with exoribonuclease activity, may play a housekeeping positive role. p53, through restriction the formation of new RNA/DNA hybrid and processing R-loop, might serve as mitochondrial R-loop suppressor. Conversely, stress-induced matrix-p53 decreases the amount of mitochondrial single-stranded RNA transcripts (including polyA- and non-polyA RNAs), thereby leading to the decline in the amount of mitochondria-encoded oxidative phosphorylation components.

Keywords:  R-loop; degradation; exonuclease; mitochondrial RNA; p53

DOI:  https://doi.org/10.1016/j.mito.2021.03.007
Int J Mol Sci. 2021 Mar 09. pii: 2746. [Epub ahead of print]22(5):

Mitochondrial Mistranslation in Brain Provokes a Metabolic Response Which Mitigates the Age-Associated Decline in Mitochondrial Gene Expression.

Dimitri Shcherbakov, Reda Juskeviciene, Adrián Cortés Sanchón, Margarita Brilkova, Hubert Rehrauer, Endre Laczko, Erik C Böttger.

  Mitochondrial misreading, conferred by mutation V338Y in mitoribosomal protein Mrps5, in-vivo is associated with a subtle neurological phenotype. Brain mitochondria of homozygous knock-in mutant Mrps5V338Y/V338Y mice show decreased oxygen consumption and reduced ATP levels. Using a combination of unbiased RNA-Seq with untargeted metabolomics, we here demonstrate a concerted response, which alleviates the impaired functionality of OXPHOS complexes in Mrps5 mutant mice. This concerted response mitigates the age-associated decline in mitochondrial gene expression and compensates for impaired respiration by transcriptional upregulation of OXPHOS components together with anaplerotic replenishment of the TCA cycle (pyruvate, 2-ketoglutarate).

Keywords:  aging; brain; metabolome; misreading; mitochondria

DOI:  https://doi.org/10.3390/ijms22052746
Life (Basel). 2021 Mar 11. pii: 232. [Epub ahead of print]11(3):

Role of Mitochondria in Viral Infections.

Srikanth Elesela, Nicholas W Lukacs.

  Viral diseases account for an increasing proportion of deaths worldwide. Viruses maneuver host cell machinery in an attempt to subvert the intracellular environment favorable for their replication. The mitochondrial network is highly susceptible to physiological and environmental insults, including viral infections. Viruses affect mitochondrial functions and impact mitochondrial metabolism, and innate immune signaling. Resurgence of host-virus interactions in recent literature emphasizes the key role of mitochondria and host metabolism on viral life processes. Mitochondrial dysfunction leads to damage of mitochondria that generate toxic compounds, importantly mitochondrial DNA, inducing systemic toxicity, leading to damage of multiple organs in the body. Mitochondrial dynamics and mitophagy are essential for the maintenance of mitochondrial quality control and homeostasis. Therefore, metabolic antagonists may be essential to gain a better understanding of viral diseases and develop effective antiviral therapeutics. This review briefly discusses how viruses exploit mitochondrial dynamics for virus proliferation and induce associated diseases.

Keywords:  MAVS; MDA5; RIG-I; RSV; SARS CoV-2; influenza; innate immune response; mitochondria; mitochondrial dynamics; viral infections

DOI:  https://doi.org/10.3390/life11030232
Mitochondrion. 2021 Mar 25. pii: S1567-7249(21)00040-4. [Epub ahead of print]

Endoplasmic Reticulum & Mitochondrial Calcium homeostasis: The Interplay with Viruses.

SwagatikaPanda, Suchismita Behera, Mohd Faraz Alam, Gulam Hussain Syed.

Calcium ions (Ca2+) act as secondary messengers in a plethora of cellular processes and play crucial role in organelle function and homeostasis. The average resting concentration of Ca2+ is nearly 100 nM and in certain cells it can reach up to 1 µM. The high range of Ca2+ concentration across the plasma membrane and intracellular Ca2+ stores demands a well-coordinated maintenance of free Ca2+ via influx, efflux, buffering and storage. Endoplasmic Reticulum and Mitochondria dependent on Ca2+ for their function and also serve as major intracellular Ca2+ stores. The ER-mitochondria interplay helps in orchestrating cellular calcium homeostasis to avoid any detrimental effect resulting from Ca2+ overload or depletion. Since it plays a central role in many biological processes it is an essential component of the virus-host interactions. The large gradient across membranes enables the viruses to easily modulate this buffered environment to meet their needs. Viruses exploit Ca2+ signaling to establish productive infection and evade the host immune defenses. In this review we will detail the interplay between the viruses and cellular & ER-mitochondrial calcium signaling and attempt to detail the significance of these events on viral life cycle and disease pathogenesis.

DOI: https://doi.org/10.1016/j.mito.2021.03.008
Int J Mol Sci. 2021 Mar 23. pii: 3245. [Epub ahead of print]22(6):

Mitochondrial Transfer in Cancer: A Comprehensive Review.

Luca X Zampieri, Catarina Silva-Almeida, Justin D Rondeau, Pierre Sonveaux.

  Depending on their tissue of origin, genetic and epigenetic marks and microenvironmental influences, cancer cells cover a broad range of metabolic activities that fluctuate over time and space. At the core of most metabolic pathways, mitochondria are essential organelles that participate in energy and biomass production, act as metabolic sensors, control cancer cell death, and initiate signaling pathways related to cancer cell migration, invasion, metastasis and resistance to treatments. While some mitochondrial modifications provide aggressive advantages to cancer cells, others are detrimental. This comprehensive review summarizes the current knowledge about mitochondrial transfers that can occur between cancer and nonmalignant cells. Among different mechanisms comprising gap junctions and cell-cell fusion, tunneling nanotubes are increasingly recognized as a main intercellular platform for unidirectional and bidirectional mitochondrial exchanges. Understanding their structure and functionality is an important task expected to generate new anticancer approaches aimed at interfering with gains of functions (e.g., cancer cell proliferation, migration, invasion, metastasis and chemoresistance) or damaged mitochondria elimination associated with mitochondrial transfer.

Keywords:  cancer; cancer metabolism; chemoresistance; metastasis; mitochondria; mitochondrial transfer; oxidative phosphorylation (OXPHOS); reactive oxygen species (ROS); tricarboxylic acid (TCA) cycle; tunneling nanotubes (TNT)

DOI:  https://doi.org/10.3390/ijms22063245