bims-midbra 2021-12-05 papers

bims-midbra

Biomed News

on Mitochondrial dynamics in brain cells

Issue of 2021‒12‒05
ten papers selected by
Ana Paula Mendonça
University of Padova

Mitochondrial dysfunction as a trigger of programmed axon death.
ER-misfolded proteins become sequestered with mitochondria and impair mitochondrial function.
Quality Control Mechanisms of Mitochondria: Another Important Target for Treatment of Peripheral Neuropathy.
Pathways shaping the mitochondrial inner membrane.
Smaug1 membrane-less organelles respond to AMPK/mTOR and affect mitochondrial function‡.
Postsynaptic autism spectrum disorder genes and synaptic dysfunction.
FAM3A Ameliorates Brain Impairment Induced by Hypoxia-Ischemia in Neonatal Rat.
Phenotypic Assay Leads to Discovery of Mitophagy Inducers with Therapeutic Potential for Parkinson's Disease.
Effects of high-intensity interval training on mitochondrial supercomplex assembly and biogenesis, mitophagy, and the AMP-activated protein kinase pathway in the soleus muscle of aged female rats.
Mitochondrial TFAM as a Signaling Regulator between Cellular Organelles: A Perspective on Metabolic Diseases.

Trends Neurosci. 2021 Nov 29. pii: S0166-2236(21)00214-9. [Epub ahead of print]

Mitochondrial dysfunction as a trigger of programmed axon death.

Elisa Merlini, Michael P Coleman, Andrea Loreto.

  Mitochondrial failure has long been associated with programmed axon death (Wallerian degeneration, WD), a widespread and potentially preventable mechanism of axon degeneration. While early findings in axotomised axons indicated that mitochondria are involved during the execution steps of this pathway, recent studies suggest that in addition, mitochondrial dysfunction can initiate programmed axon death without physical injury. As mitochondrial dysfunction is associated with disorders involving early axon loss, including Parkinson's disease, peripheral neuropathies, and multiple sclerosis, the findings that programmed axon death is activated by mitochondrial impairment could indicate the involvement of druggable mechanisms whose disruption may protect axons in such diseases. Here, we review the latest developments linking mitochondrial dysfunction to programmed axon death and discuss their implications for injury and disease.

Keywords:  Parkinson’s disease; SARM1; Wallerian degeneration; axon degeneration; mitochondrial dysfunction; programmed axon death

DOI:  https://doi.org/10.1016/j.tins.2021.10.014
Commun Biol. 2021 Dec 02. 4(1): 1350

ER-misfolded proteins become sequestered with mitochondria and impair mitochondrial function.

Adrián Cortés Sanchón, Harshitha Santhosh Kumar, Matilde Mantovani, Ivan Osinnii, José María Mateos, Andres Kaech, Dimitri Shcherbakov, Rashid Akbergenov, Erik C Böttger.

Proteostasis is a challenge for cellular organisms, as all known protein synthesis machineries are error-prone. Here we show by cell fractionation and microscopy studies that misfolded proteins formed in the endoplasmic reticulum can become associated with and partly transported into mitochondria, resulting in impaired mitochondrial function. Blocking the endoplasmic reticulum-mitochondria encounter structure (ERMES), but not the mitochondrial sorting and assembly machinery (SAM) or the mitochondrial surveillance pathway components Msp1 and Vms1, abrogated mitochondrial sequestration of ER-misfolded proteins. We term this mitochondria-associated proteostatic mechanism for ER-misfolded proteins ERAMS (ER-associated mitochondrial sequestration). We testify to the relevance of this pathway by using mutant α-1-antitrypsin as an example of a human disease-related misfolded ER protein, and we hypothesize that ERAMS plays a role in pathological features such as mitochondrial dysfunction.

DOI: https://doi.org/10.1038/s42003-021-02873-w
DNA Cell Biol. 2021 Dec 01.

Quality Control Mechanisms of Mitochondria: Another Important Target for Treatment of Peripheral Neuropathy.

Te Zhang, Jiannan Li, Guoqing Zhao.

  Mitochondria provide energy for various cellular activities and are involved in the regulating of several physiological and pathological processes. Mitochondria constitute a dynamic network regulated by numerous quality control mechanisms; for example, division is necessary for mitochondria to develop, and fusion dilutes toxins produced by the mitochondria. Mitophagy removes damaged mitochondria. The etiologies of peripheral neuropathy include congenital and acquired diseases, and the pathogenesis varies; however, oxidative stress caused by mitochondrial damage is the accepted pathogenesis of peripheral neuropathy. Regulation and control of mitochondrial quality might point the way toward potential treatments for peripheral neuropathy. This article will review mitochondrial quality control mechanisms, their involvement in peripheral nerve diseases, and their potential therapeutic role.

Keywords:  mitochondria; mitochondrial dynamics; mitophagy; pain; peripheral neuropathy

DOI:  https://doi.org/10.1089/dna.2021.0529
Open Biol. 2021 Dec;11(12): 210238

Pathways shaping the mitochondrial inner membrane.

Till Klecker, Benedikt Westermann.

  Mitochondria are complex organelles with two membranes. Their architecture is determined by characteristic folds of the inner membrane, termed cristae. Recent studies in yeast and other organisms led to the identification of four major pathways that cooperate to shape cristae membranes. These include dimer formation of the mitochondrial ATP synthase, assembly of the mitochondrial contact site and cristae organizing system (MICOS), inner membrane remodelling by a dynamin-related GTPase (Mgm1/OPA1), and modulation of the mitochondrial lipid composition. In this review, we describe the function of the evolutionarily conserved machineries involved in mitochondrial cristae biogenesis with a focus on yeast and present current models to explain how their coordinated activities establish mitochondrial membrane architecture.

Keywords:  ATP synthase; MICOS; Mgm1; Saccharomyces cerevisiae; cristae; mitochondrial lipids

DOI:  https://doi.org/10.1098/rsob.210238
J Cell Sci. 2021 Dec 03. pii: jcs.253591. [Epub ahead of print]

Smaug1 membrane-less organelles respond to AMPK/mTOR and affect mitochondrial function‡.

Ana J Fernández-Alvarez, María Gabriela Thomas, Malena L Pascual, Martín Habif, Jerónimo Pimentel, Agustín A Corbat, João P Pessoa, Pablo E La Spina, Lara Boscaglia, Anne Plessis, Maria Carmo-Fonseca, Hernán E Grecco, Marta Casado, Graciela L Boccaccio.

  Smaug is a conserved translational regulator that binds numerous mRNAs, including nuclear transcripts that encode mitochondrial enzymes. Smaug orthologs form cytosolic membrane-less organelles (MLOs) in several organisms and cell types. We have performed single-molecule FISH assays that revealed that SDHB and UQCRC1 mRNAs associate with Smaug1 bodies in U2OS cells. Loss of function of Smaug1 and Smaug2 affected both mitochondrial respiration and morphology of the mitochondrial network. Phenotype rescue by Smaug1 transfection depends on the presence of its RNA binding domain. Moreover, we identified specific Smaug1 domains involved in MLO formation, and found that impaired Smaug1 MLO condensation correlates with mitochondrial defects. Mitochondrial Complex I inhibition by rotenone -but not strong mitochondrial uncoupling by CCCP- rapidly induced Smaug1 MLOs dissolution. Metformin and rapamycin elicited similar effects, which were blocked by pharmacological inhibition of AMPK. Finally, we found that Smaug1 MLO dissolution weakens the interaction with target mRNAs, thus enabling their release. We propose that mitochondrial respiration and the AMPK/mTOR balance controls the condensation and dissolution of Smaug1 MLOs, thus regulating nuclear mRNAs that encode key mitochondrial proteins.

Keywords:  AMPK; Membrane-less organelles; Metformin; Mitochondria; Processing bodies; Smaug; Uqcrc1

DOI:  https://doi.org/10.1242/jcs.253591
Neurobiol Dis. 2021 Nov 24. pii: S0969-9961(21)00313-2. [Epub ahead of print]162 105564

Postsynaptic autism spectrum disorder genes and synaptic dysfunction.

Paola Bonsi, Antonella De Jaco, Laurent Fasano, Paolo Gubellini.

  This review provides an overview of the synaptic dysfunction of neuronal circuits and the ensuing behavioral alterations caused by mutations in autism spectrum disorder (ASD)-linked genes directly or indirectly affecting the postsynaptic neuronal compartment. There are plenty of ASD risk genes, that may be broadly grouped into those involved in gene expression regulation (epigenetic regulation and transcription) and genes regulating synaptic activity (neural communication and neurotransmission). Notably, the effects mediated by ASD-associated genes can vary extensively depending on the developmental time and/or subcellular site of expression. Therefore, in order to gain a better understanding of the mechanisms of disruptions in postsynaptic function, an effort to better model ASD in experimental animals is required to improve standardization and increase reproducibility within and among studies. Such an effort holds promise to provide deeper insight into the development of these disorders and to improve the translational value of preclinical studies.

Keywords:  ASD gene expression regulation; Animal models of ASD; Mitochondrial dysfunction

DOI:  https://doi.org/10.1016/j.nbd.2021.105564
Cell Mol Neurobiol. 2021 Dec 01.

FAM3A Ameliorates Brain Impairment Induced by Hypoxia-Ischemia in Neonatal Rat.

Qing Song, Qingying Gao, Taotao Chen, Ting Wen, Peng Wu, Xiao Luo, Qiao Yi Chen.

  Hypoxia-ischemia (HI) during crucial periods of brain formation can lead to changes in brain morphology, propagation of neuronal stimuli, and permanent neurodevelopmental impairment, which can have profound effects on cognitive function later in life. FAM3A, a subgroup of family with sequence similarity 3 (FAM3) gene family, is ubiquitously expressed in almost all cells. Overexpression of FAM3A has been evidenced to reduce hyperglycemia via the PI3K/Akt signaling pathway and protect mitochondrial function in neuronal HT22 cells. This study aims to evaluate the protective role of FAM3A in HI-induced brain impairment. Experimentally, maternal rats underwent uterine artery bilateral ligation to induce neonatal HI on day 14 of gestation. At 6 weeks of age, cognitive development assessments including NSS, wire grip, and water maze were carried out. The animals were then sacrificed to assess cerebral mitochondrial function as well as levels of FAM3A, TNF-α and IFN-γ. Results suggest that HI significantly reduced FAM3A expression in rat brain tissues, and that overexpression of FAM3A through lentiviral transduction effectively improved cognitive and motor functions in HI rats as reflected by improved NSS evaluation, cerebral water content, limb strength, as well as spatial learning and memory. At the molecular level, overexpression of FAM3A was able to promote ATP production, balance mitochondrial membrane potential, and reduce levels of pro-inflammatory cytokines TNF-α and IFN-γ. We conclude that FAM3A overexpression may have a protective effect on neuron morphology, cerebral mitochondrial as well as cognitive function. Created with Biorender.com.

Keywords:  Brain; FAM3A; Hypoxia–ischemia; IFN-γ; Mitochondria; TNF-α

DOI:  https://doi.org/10.1007/s10571-021-01172-6
ACS Chem Neurosci. 2021 Nov 30.

Phenotypic Assay Leads to Discovery of Mitophagy Inducers with Therapeutic Potential for Parkinson's Disease.

Inés Maestro, Laura R de la Ballina, Anne Simonsen, Patricia Boya, Ana Martinez.

  Mitophagy, the selective degradation of mitochondria by autophagy, involved in important physiological processes and defects in pathways has been reported in pathological conditions, such as neurodegeneration. Thus, mitophagy is an interesting target for drug discovery programs. In this investigation, we used robust phenotypic assay to screen a set of 50 small heterocyclic compounds to identify inducers of mitophagy. We identified two compounds, VP07 and JAR1.39, that induce Parkin-dependent mitophagy. Based on structure-activity relationship studies, we proposed the ability of the compounds to act as light chain 3 (LC3) interactors, similar to cardiolipin or ceramide, triggering mitophagy via Pink1/Parkin. Finally, we show promising therapeutic applicability in a cellular model of Parkinson's disease.

Keywords:  Parkinson’s disease; drug discovery; mitophagy; mitophagy inducers; phenotypic assay

DOI:  https://doi.org/10.1021/acschemneuro.1c00529
Exp Gerontol. 2021 Nov 30. pii: S0531-5565(21)00430-7. [Epub ahead of print] 111648

Effects of high-intensity interval training on mitochondrial supercomplex assembly and biogenesis, mitophagy, and the AMP-activated protein kinase pathway in the soleus muscle of aged female rats.

Chong Han, Peng Lu, Shi-Zhan Yan.

  PURPOSE: Exercise helps improve mitochondrial function to combat sarcopenia. Certain parts of the mitochondrial respiratory chain complex can form a higher-order structure called "supercomplex" to reduce the production of reactive oxygen species and improve muscle mass. The effect of exercise on the assembly of the mitochondrial supercomplex is still unclear. The aim of this study was to investigate the effects of long-term high-intensity interval training (HIIT) on mitochondrial biogenesis, mitophagy, and mitochondrial supercomplexes (mitoSCs) assembly in aging soleus muscle.METHODS: Female Sprague-Dawley rats (n = 36) were randomly divided into four groups: young sedentary (Y-SED, 8 months old, n = 12), old sedentary (O-SED, 26 months old, n = 12), moderate-intensity continuous training (MICT, from 18 to 26 months old, n = 12), and HIIT (from 18 to 26 months old, n = 12). Rats in the MICT and HIIT groups were subjected to an 8-month training program. Real-time fluorescent quantitative polymerase chain reaction was used to measure the expression of the antioxidative factors, inflammatory factors, and mitochondrial fusion- and division-related genes. Western blotting was used to detect the expression of mitochondrial biogenesis and mitophagy markers and AMP-activated protein kinase (AMPK) pathway proteins. Enzyme-linked immunosorbent assays were used to determine serum irisin contents. Blue native polyacrylamide gel electrophoresis was used to assess the formation of mitochondrial supercomplexes.
RESULTS: Compared with the Y-SED group, the soleus muscle and mitochondria in the O-SED group showed reduced expression of mitophagy- and mitochondrial biogenesis-related proteins. In the HIIT group, the expression of autophagy-related proteins in the soleus muscle and mitochondria was significantly increased compared with that in the MICT group. Serum irisin and mitochondrial fusion protein levels significantly decreased with age. Superoxide dismutase 2 protein levels and AMPK pathway protein expression were significantly increased in the HIIT group compared with those in the other groups. Additionally, the expression levels of mitoSCs and the mRNA levels of interleukin-15 and optical atrophy 1 increased in the HIIT group compared with that in the MICT group.
CONCLUSION: Compared with MICT, HIIT activated the AMPK pathway to upregulate mitochondrial biogenesis- and mitophagy-related proteins, and promote the assembly and formation of mitoSCs to improve the mitochondrial function of aging soleus muscles.

Keywords:  AMPK pathway; High-intensity interval training, aging; Mitochondrial supercomplex; Mitophagy

DOI:  https://doi.org/10.1016/j.exger.2021.111648
Diabetes Metab J. 2021 Nov;45(6): 853-865

Mitochondrial TFAM as a Signaling Regulator between Cellular Organelles: A Perspective on Metabolic Diseases.

Jin-Ho Koh, Yong-Woon Kim, Dae-Yun Seo, Tae-Seo Sohn.

  Tissues actively involved in energy metabolism are more likely to face metabolic challenges from bioenergetic substrates and are susceptible to mitochondrial dysfunction, leading to metabolic diseases. The mitochondria receive signals regarding the metabolic states in cells and transmit them to the nucleus or endoplasmic reticulum (ER) using calcium (Ca2+) for appropriate responses. Overflux of Ca2+ in the mitochondria or dysregulation of the signaling to the nucleus and ER could increase the incidence of metabolic diseases including insulin resistance and type 2 diabetes mellitus. Mitochondrial transcription factor A (Tfam) may regulate Ca2+ flux via changing the mitochondrial membrane potential and signals to other organelles such as the nucleus and ER. Since Tfam is involved in metabolic function in the mitochondria, here, we discuss the contribution of Tfam in coordinating mitochondria-ER activities for Ca2+ flux and describe the mechanisms by which Tfam affects mitochondrial Ca2+ flux in response to metabolic challenges.

Keywords:  Calcium; Cell nucleus; Diabetes mellitus, type 2; Endoplasmic reticulum; Mitochondria; TFAM protein

DOI:  https://doi.org/10.4093/dmj.2021.0138