bims-mecmid 2021-11-28 papers

bims-mecmid

Biomed News

on Membrane communication in mitochondrial dynamics

Issue of 2021–11–28
nine papers selected by
Mauricio Cardenas Rodriguez, University of Padova

The role of protein acetylation in regulating mitochondrial fusion and fission.
The Molecular Assembly State of Drp1 Controls its Association With the Mitochondrial Recruitment Receptors Mff and MIEF1/2.
Dose-Dependent Response to the Environmental Pollutant Dichlorodipheniletylhene (DDE) in HepG2 Cells: Focus on Cell Viability and Mitochondrial Fusion/Fission Proteins.
Acetylation in Mitochondria Dynamics and Neurodegeneration.
ER-associated CTRP1 regulates mitochondrial fission via interaction with DRP1.
The Multifaceted Regulation of Mitochondrial Dynamics During Mitosis.
Mitochondrial Quality Control in the Maintenance of Cardiovascular Homeostasis: The Roles and Interregulation of UPS, Mitochondrial Dynamics and Mitophagy.
Nrf2 contributes to the benefits of exercise interventions on age-related skeletal muscle disorder via regulating Drp1 stability and mitochondrial fission.
An MFN2-related Charcot-Marie-Tooth Disease Patient with Optic Nerve Atrophy, Neurogenic Bladder Dysfunction, and Diaphragmatic Weakness.

Biochem Soc Trans. 2021 Nov 23. pii: BST20210798. [Epub ahead of print]

The role of protein acetylation in regulating mitochondrial fusion and fission.

Golam M Uddin, Rafa Abbas, Timothy E Shutt.

  The dynamic processes of mitochondrial fusion and fission determine the shape of mitochondria, which can range from individual fragments to a hyperfused network, and influence mitochondrial function. Changes in mitochondrial shape can occur rapidly, allowing mitochondria to adapt to specific cues and changing cellular demands. Here, we will review what is known about how key proteins required for mitochondrial fusion and fission are regulated by their acetylation status, with acetylation promoting fission and deacetylation enhancing fusion. In particular, we will examine the roles of NAD+ dependant sirtuin deacetylases, which mediate mitochondrial acetylation, and how this post-translational modification provides an exquisite regulatory mechanism to co-ordinate mitochondrial function with metabolic demands of the cell.

Keywords:  acetylation/deacetylation; fission; fusion; mitochondria; sirtuins

DOI:  https://doi.org/10.1042/BST20210798
Front Cell Dev Biol. 2021 ;9 706687

The Molecular Assembly State of Drp1 Controls its Association With the Mitochondrial Recruitment Receptors Mff and MIEF1/2.

Rong Yu, Shao-Bo Jin, Maria Ankarcrona, Urban Lendahl, Monica Nistér, Jian Zhao.

  Drp1 is a central player in mitochondrial fission and is recruited to mitochondria by Mff and MIEFs (MIEF1 and MIEF2), but little is known about how its assembly state affects Drp1 mitochondrial recruitment and fission. Here, we used in vivo chemical crosslinking to explore the self-assembly state of Drp1 and how it regulates the association of Drp1 with MIEFs and Mff. We show that in intact mammalian cells Drp1 exists as a mixture of multiple self-assembly forms ranging from the minimal, probably tetrameric, self-assembly subunit to several higher order oligomers. Precluding mitochondria-bound Drp1 in Mff/MIEF1/2-deficient cells does not affect the oligomerization state of Drp1, while conversely forced recruitment of Drp1 to mitochondria by MIEFs or Mff facilitates Drp1 oligomerization. Mff preferentially binds to higher order oligomers of Drp1, whereas MIEFs bind to a wider-range of Drp1 assembly subunits, including both lower and higher oligomeric states. Mff only recruits active forms of Drp1, while MIEFs are less selective and recruit both active and inactive Drp1 as well as oligomerization- or GTPase-deficient Drp1 mutants to mitochondria. Moreover, all the fission-incompetent Drp1 mutants tested (except the monomeric mutant K668E) affect Drp1-driven mitochondrial dynamics via incorporation of the mutants into the native oligomers to form function-deficient Drp1 assemblies. We here confirm that MIEFs also serve as a platform facilitating the binding of Drp1 to Mff and loss of MIEFs severely impairs the interaction between Drp1 and Mff. Collectively, our findings suggest that Mff and MIEFs respond differently to the molecular assembly state of Drp1 and that the extent of Drp1 oligomerization regulates mitochondrial dynamics.

Keywords:  Drp1; Drp1 mutation; MIEF1; MIEF2; Mff; mitochondria; mitochondrial dynamics; oligomerization

DOI:  https://doi.org/10.3389/fcell.2021.706687
Toxics. 2021 Oct 20. pii: 270. [Epub ahead of print]9(11):

Dose-Dependent Response to the Environmental Pollutant Dichlorodipheniletylhene (DDE) in HepG2 Cells: Focus on Cell Viability and Mitochondrial Fusion/Fission Proteins.

Mario Alberto Burgos Aceves, Vincenzo Migliaccio, Marilena Lepretti, Gaetana Paolella, Ilaria Di Gregorio, Serena Penna, Caterina Faggio, Lillà Lionetti.

  Dichlorodiphenyldichloroethylene (DDE), the primary persistent metabolite of dichlorodiphenyltrichloroethane (DDT), has toxic effects on cells, but its dose-dependent impact on mitochondrial proteins involved in mitochondrial fusion and fission processes associated with cell viability impairment has not yet been analysed. Mitochondrial fusion and fission processes are critical to maintaining the mitochondrial network and allowing the cell to respond to external stressors such as environmental pollutants. Fusion processes are associated with optimizing mitochondrial function, whereas fission processes are associated with removing damaged mitochondria. We assessed the effects of different DDE doses, ranging between 0.5 and 100 µM, on cell viability and mitochondrial fusion/fission proteins in an in vitro hepatic cell model (human hepatocarcinomatous cells, HepG2); the DDE induced a decrease in cell viability in a dose-dependent manner, and its effect was enhanced in conditions of coincubation with dietary fatty acids. Fusion protein markers exhibited an inverted U-shape dose-response curve, showing the highest content in the 2.5-25 μM DDE dose range. The fission protein marker was found to increase significantly, leading to an increased fission/fusion ratio with high DDE doses. The low DDE doses elicited cell adaption by stimulating mitochondrial dynamics machinery, whereas high DDE doses induced cell viability loss associated with mitochondrial dynamics to shift toward fission. Present results are helpful to clarify the mechanisms underlying the cell fate towards survival or death in response to increasing doses of environmental pollutants.

Keywords:  DRP1; Mfn2; SOD; environmental pollutants; hepatocytes; mitochondria

DOI:  https://doi.org/10.3390/toxics9110270
Cells. 2021 Nov 05. pii: 3031. [Epub ahead of print]10(11):

Acetylation in Mitochondria Dynamics and Neurodegeneration.

Jaylyn Waddell, Aditi Banerjee, Tibor Kristian.

  Mitochondria are a unique intracellular organelle due to their evolutionary origin and multifunctional role in overall cellular physiology and pathophysiology. To meet the specific spatial metabolic demands within the cell, mitochondria are actively moving, dividing, or fusing. This process of mitochondrial dynamics is fine-tuned by a specific group of proteins and their complex post-translational modifications. In this review, we discuss the mitochondrial dynamics regulatory enzymes, their adaptor proteins, and the effect of acetylation on the activity of fusion and fission machinery as a ubiquitous response to metabolic stresses. Further, we discuss the role of intracellular cytoskeleton structures and their post-translational modifications in the modulation of mitochondrial fusion and fission. Finally, we review the role of mitochondrial dynamics dysregulation in the pathophysiology of acute brain injury and the treatment strategies based on modulation of NAD+-dependent deacetylation.

Keywords:  acetylation; dynamics; mitochondria; tubulin

DOI:  https://doi.org/10.3390/cells10113031
Exp Mol Med. 2021 Nov 26.

ER-associated CTRP1 regulates mitochondrial fission via interaction with DRP1.

Seong Keun Sonn, Seungwoon Seo, Jaemoon Yang, Ki Sook Oh, Hsiuchen Chen, David C Chan, Kunsoo Rhee, Kyung S Lee, Young Yang, Goo Taeg Oh.

C1q/TNF-related protein 1 (CTRP1) is a CTRP family member that has collagenous and globular C1q-like domains. The secreted form of CTRP1 is known to be associated with cardiovascular and metabolic diseases, but its cellular roles have not yet been elucidated. Here, we showed that cytosolic CTRP1 localizes to the endoplasmic reticulum (ER) membrane and that knockout or depletion of CTRP1 leads to mitochondrial fission defects, as demonstrated by mitochondrial elongation. Mitochondrial fission events are known to occur through an interaction between mitochondria and the ER, but we do not know whether the ER and/or its associated proteins participate directly in the entire mitochondrial fission event. Interestingly, we herein showed that ablation of CTRP1 suppresses the recruitment of DRP1 to mitochondria and provided evidence suggesting that the ER-mitochondrion interaction is required for the proper regulation of mitochondrial morphology. We further report that CTRP1 inactivation-induced mitochondrial fission defects induce apoptotic resistance and neuronal degeneration, which are also associated with ablation of DRP1. These results demonstrate for the first time that cytosolic CTRP1 is an ER transmembrane protein that acts as a key regulator of mitochondrial fission, providing new insight into the etiology of metabolic and neurodegenerative disorders.

DOI: https://doi.org/10.1038/s12276-021-00701-z
Front Cell Dev Biol. 2021 ;9 767221

The Multifaceted Regulation of Mitochondrial Dynamics During Mitosis.

Evanthia Pangou, Izabela Sumara.

  Mitosis ensures genome integrity by mediating precise segregation of the duplicated genetic material. Segregation of subcellular organelles during mitosis also needs to be tightly coordinated in order to warrant their proper inheritance and cellular homeostasis. The inheritance of mitochondria, a powerhouse of the cell, is tightly regulated in order to meet the high energy demand to fuel the mitotic machinery. Mitochondria are highly dynamic organelles, which undergo events of fission, fusion and transport during different cell cycle stages. Importantly, during mitosis several kinases phosphorylate the key mitochondrial factors and drive fragmentation of mitochondria to allow for their efficient distribution and inheritance to two daughter cells. Recent evidence suggests that mitochondrial fission can also actively contribute to the regulation of mitotic progression. This review aims at summarizing established and emerging concepts about the complex regulatory networks which couple crucial mitotic factors and events to mitochondrial dynamics and which could be implicated in human disease.

Keywords:  disease; fission; fusion; mitochondria; mitosis; transport

DOI:  https://doi.org/10.3389/fcell.2021.767221
Oxid Med Cell Longev. 2021 ;2021 3960773

Mitochondrial Quality Control in the Maintenance of Cardiovascular Homeostasis: The Roles and Interregulation of UPS, Mitochondrial Dynamics and Mitophagy.

Yujie Song, Yuerong Xu, Yingying Liu, Jie Gao, Lele Feng, Yuxi Zhang, Lei Shi, Miao Zhang, Dong Guo, Bingchao Qi, Mingming Zhang.

Maintenance of normal function of mitochondria is vital to the fate and health of cardiomyocytes. Mitochondrial quality control (MQC) mechanisms are essential in governing mitochondrial integrity and function. The ubiquitin-proteasome system (UPS), mitochondrial dynamics, and mitophagy are three major components of MQC. With the progress of research, our understanding of MQC mechanisms continues to deepen. Gradually, we realize that the three MQC mechanisms are not independent of each other. To the contrary, there are crosstalk among the mechanisms, which can make them interact with each other and cooperate well, forming a triangle interplay. Briefly, the UPS system can regulate the level of mitochondrial dynamic proteins and mitophagy receptors. In the process of Parkin-dependent mitophagy, the UPS is also widely activated, performing critical roles. Mitochondrial dynamics have a profound influence on mitophagy. In this review, we provide new processes of the three major MQC mechanisms in the background of cardiomyocytes and delve into the relationship between them.

DOI: https://doi.org/10.1155/2021/3960773
Free Radic Biol Med. 2021 Nov 22. pii: S0891-5849(21)00828-5. [Epub ahead of print]

Nrf2 contributes to the benefits of exercise interventions on age-related skeletal muscle disorder via regulating Drp1 stability and mitochondrial fission.

Xialin Yan, Zile Shen, Dingye Yu, Chongke Zhao, Hongbo Zou, Bingwei Ma, Wenxi Dong, Wenhao Chen, Dongdong Huang, Zhen Yu.

  The progressive and generalized loss of skeletal muscle mass and function, also known as sarcopenia, underlies disability, increasing adverse outcomes and poor quality of life in older people. Exercise interventions are commonly recommended as the primary treatment for sarcopenia. Nuclear factor erythroid 2-related factor 2 (Nrf2) plays a vital role in regulating metabolism, mitochondrial function, and the ROS-dependent adaptations of skeletal muscle, as the response to exercise. To investigate the contribution of Nrf2 to the benefits of exercise interventions in older age, aged (∼22 month old) Nrf2 knockout (Nrf2-KO) mice and age-matched wild-type (WT) C57Bl6/J mice were randomly divided into 2 groups (sedentary or exercise group). We found that exercise interventions improved skeletal muscle function and restored the sarcopenia-like phenotype in WT mice, accompanied with the increasing mRNA level of Nrf2. While these alternations were minimal in Nrf2-KO mice after exercise. Further studies indicated that Nrf2 could increase the stability of Drp1 through deubiquitinating and promote Drp1-dependent mitochondrial fission to attenuate mitochondrial disorder. We also observed the effects of sulforaphane (SFN), a Nrf2 activator, in restoring mitochondrial function in senescent C2C12 cells and improving sarcopenia in older WT mice, which were abolished by Nrf2 deficiency. These results indicated that some benefits of exercise intervention to skeletal muscle were Nrf2 mediated, and a future work should focus on Nrf2 signaling to identify a pharmacological treatment for sarcopenia.

Keywords:  Aging; Drp1; Mitochondrial fission; Nrf2; Sarcopenia

DOI:  https://doi.org/10.1016/j.freeradbiomed.2021.11.030
Intern Med. 2021 Nov 20.

An MFN2-related Charcot-Marie-Tooth Disease Patient with Optic Nerve Atrophy, Neurogenic Bladder Dysfunction, and Diaphragmatic Weakness.

Yasuyoshi Kimura, Akira Nishikawa, Akihiro Hashiguchi, Masaki Etoh, Akiko Yoshimura, Kanako Asai, Noriko Miyashita, Hiroshi Takashima, Hisae Sumi, Takashi Naka.

  Charcot-Marie-Tooth disease (CMT) is a common hereditary peripheral polyneuropathy encompassing distinct monogenetic disorders. Pathogenic mutations in mitofusin 2 (MFN2) are the most frequent cause of its axonal type, CMT type 2A, with diverse phenotypes. We herein report a Japanese patient with a novel heterozygous MFN2 pathogenic variant (c.740 G>C, p.R247P) and severe CMT phenotypes, including progressive muscle weakness, optic atrophy, urinary inconsistency, and restrictive pulmonary dysfunction with eventration of the diaphragm that developed over her 60-year disease course. Our case expands the clinico-genetic features of MFN2-related CMT and highlights the need to evaluate infrequent manifestations during long-term care of CMT patients.

Keywords:  Charcot-Marie-Tooth disease; Hereditary Motor Sensory Neuropathy; Mitofusin 2; diaphragmatic weakness; neurogenic bladder; restrictive pulmonary dysfunction

DOI:  https://doi.org/10.2169/internalmedicine.6487-20