bims-mitdyn Biomed News
on Mitochondrial dynamics: mechanisms
Issue of 2021‒04‒04
ten papers selected by
Edmond Chan
Queen’s University, School of Medicine
  1. Selective packaging of mitochondrial proteins into extracellular vesicles prevents the release of mitochondrial DAMPs.
  2. Selective autophagy of AKAP11 activates cAMP/PKA to fuel mitochondrial metabolism and tumor cell growth.
  3. Genome-wide RNAi screen for regulators of UPRmt in Caenorhabditis elegans mutants with defects in mitochondrial fusion.
  4. Opa1 relies on cristae preservation and ATP synthase to curtail reactive oxygen species accumulation in mitochondria.
  5. KRT8 (keratin 8) attenuates necrotic cell death by facilitating mitochondrial fission-mediated mitophagy through interaction with PLEC (plectin).
  6. Imaging Mitochondrial Dynamics in the Xenopus Central Nervous System (CNS).
  7. Genetic Neuropathy Due to Impairments in Mitochondrial Dynamics.
  8. Mitochondrial quality control: from molecule to organelle.
  9. Role of Mitochondria in Viral Infections.
  10. Could mitochondria help athletes to make gains?
  1. 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
  2. Proc Natl Acad Sci U S A. 2021 Apr 06. pii: e2020215118. [Epub ahead of print]118(14):
    Selective autophagy of AKAP11 activates cAMP/PKA to fuel mitochondrial metabolism and tumor cell growth.
    Zhiqiang Deng, Xianting Li, Marian Blanca Ramirez, Kerry Purtell, Insup Choi, Jia-Hong Lu, Qin Yu, Zhenyu Yue.
      Autophagy is a catabolic pathway that provides self-nourishment and maintenance of cellular homeostasis. Autophagy is a fundamental cell protection pathway through metabolic recycling of various intracellular cargos and supplying the breakdown products. Here, we report an autophagy function in governing cell protection during cellular response to energy crisis through cell metabolic rewiring. We observe a role of selective type of autophagy in direct activation of cyclic AMP protein kinase A (PKA) and rejuvenation of mitochondrial function. Mechanistically, autophagy selectively degrades the inhibitory subunit RI of PKA holoenzyme through A-kinase-anchoring protein (AKAP) 11. AKAP11 acts as an autophagy receptor that recruits RI to autophagosomes via LC3. Glucose starvation induces AKAP11-dependent degradation of RI, resulting in PKA activation that potentiates PKA-cAMP response element-binding signaling, mitochondria respiration, and ATP production in accordance with mitochondrial elongation. AKAP11 deficiency inhibits PKA activation and impairs cell survival upon glucose starvation. Our results thus expand the view of autophagy cytoprotection mechanism by demonstrating selective autophagy in RI degradation and PKA activation that fuels the mitochondrial metabolism and confers cell resistance to glucose deprivation implicated in tumor growth.
    Keywords:  AKAP11; PKA; autophagy; cell survival; mitochondrial metabolism
    DOI:  https://doi.org/10.1073/pnas.2020215118
  3. 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
  4. 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
  5. 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
  6. Cold Spring Harb Protoc. 2021 Apr 01. 2021(4): pdb.prot106807
    Imaging Mitochondrial Dynamics in the Xenopus Central Nervous System (CNS).
    Martin Sihan Feng, Jennifer E Bestman.
      Notable for producing ATP via oxidative phosphorylation, mitochondria also control calcium homeostasis, lipogenesis, the regulation of reactive oxygen species, and apoptosis. Even within relatively simple cells, mitochondria are heterogeneous with regard to their shape, abundance, movement, and subcellular locations. They exist as interconnected, tubular networks and as motile organelles that are transported along the cytoskeleton for distribution throughout cells. These spatial and morphological features reflect variability in the organelle's capacity to synthesize ATP and support cells. Changes to mitochondria are believed to support cell function and fate, and mitochondrial dysfunction underlies disease in the nervous system. Here we describe an in vivo time-lapse imaging approach to monitor and measure the movement and position of the mitochondria in cells of the developing brain in albino Xenopus laevis tadpoles. The unparalleled benefit of using Xenopus for these experiments is that measurements of mitochondrial morphology and distribution in cells can be measured in vivo, where the surrounding neural circuitry and other inputs that influence these critical organelles remain intact. This protocol draws together techniques to label brain cells and capture the morphology of the cells and their mitochondria with 3D time-lapse confocal microscopy. We describe open-source methods to reconstruct cells in order to quantify the features of their mitochondria.
    DOI:  https://doi.org/10.1101/pdb.prot106807
  7. Biology (Basel). 2021 Mar 26. pii: 268. [Epub ahead of print]10(4):
    Genetic Neuropathy Due to Impairments in Mitochondrial Dynamics.
    Govinda Sharma, Gerald Pfeffer, Timothy E Shutt.
      Mitochondria are dynamic organelles capable of fusing, dividing, and moving about the cell. These properties are especially important in neurons, which in addition to high energy demand, have unique morphological properties with long axons. Notably, mitochondrial dysfunction causes a variety of neurological disorders including peripheral neuropathy, which is linked to impaired mitochondrial dynamics. Nonetheless, exactly why peripheral neurons are especially sensitive to impaired mitochondrial dynamics remains somewhat enigmatic. Although the prevailing view is that longer peripheral nerves are more sensitive to the loss of mitochondrial motility, this explanation is insufficient. Here, we review pathogenic variants in proteins mediating mitochondrial fusion, fission and transport that cause peripheral neuropathy. In addition to highlighting other dynamic processes that are impacted in peripheral neuropathies, we focus on impaired mitochondrial quality control as a potential unifying theme for why mitochondrial dysfunction and impairments in mitochondrial dynamics in particular cause peripheral neuropathy.
    Keywords:  fission; fusion; mitochondria; mitochondrial dynamics; neuropathy; quality control; transport
    DOI:  https://doi.org/10.3390/biology10040268
  8. 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
  9. 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
  10. Nature. 2021 Apr;592(7852): S7-S9
    Could mitochondria help athletes to make gains?
    Anthony King.
      
    Keywords:  Cell biology; Physiology
    DOI:  https://doi.org/10.1038/d41586-021-00817-2
This page is being maintained by Thomas Krichel. It was last updated on 2021‒07‒23 at 10:22:22.