bims-midbra 2021-12-12 papers

bims-midbra

Biomed News

on Mitochondrial dynamics in brain cells

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

PINK1 overexpression prevents forskolin-induced tau hyperphosphorylation and oxidative stress in a rat model of Alzheimer's disease.
MITOL-mediated DRP1 ubiquitylation and degradation promotes mitochondrial hyperfusion in CMT2A-linked MFN2 mutant.
Regulation of neuronal autophagy and the implications in neurodegenerative diseases.
The Role of Mitochondria in Optic Atrophy With Autosomal Inheritance.
Live-imaging of Mitochondrial System in Cultured Astrocytes.
Mitochondrial Biogenesis in Neurons: How and Where.
Mitochondria-Related Nuclear Gene Expression in the Nucleus Accumbens and Blood Mitochondrial Copy Number After Developmental Fentanyl Exposure in Adolescent Male and Female C57BL/6 Mice.

Acta Pharmacol Sin. 2021 Dec 10.

PINK1 overexpression prevents forskolin-induced tau hyperphosphorylation and oxidative stress in a rat model of Alzheimer's disease.

Xiao-Juan Wang, Lin Qi, Ya-Fang Cheng, Xue-Fei Ji, Tian-Yan Chi, Peng Liu, Li-Bo Zou.

  PTEN-induced putative kinase 1 (PINK1)/parkin pathway mediates mitophagy, which is a specialized form of autophagy. Evidence shows that PINK1 can exert protective effects against stress-induced neuronal cell death. In the present study we investigated the effects of PINK1 overexpression on tau hyperphosphorylation, mitochondrial dysfunction and oxidative stress in a specific rat model of tau hyperphosphorylation. We showed that intracerebroventricular (ICV) microinjection of forskolin (FSK, 80 μmol) induced tau hyperphosphorylation in the rat brain and resulted in significant spatial working memory impairments in Y-maze test, accompanied by synaptic dysfunction (reduced expression of synaptic proteins synaptophysin and postsynaptic density protein 95), and neuronal loss in the hippocampus. Adeno-associated virus (AAV)-mediated overexpression of PINK1 prevented ICV-FSK-induced cognition defect and pathological alterations in the hippocampus, whereas PINK1-knockout significantly exacerbated ICV-FSK-induced deteriorated effects. Furthermore, we revealed that AAV-PINK1-mediated overexpression of PINK1 alleviated ICV-FSK-induced tau hyperphosphorylation by restoring the activity of PI3K/Akt/GSK3β signaling. PINK1 overexpression reversed the abnormal changes in mitochondrial dynamics, defective mitophagy, and decreased ATP levels in the hippocampus. Moreover, PINK1 overexpression activated Nrf2 signaling, thereby increasing the expression of antioxidant proteins and reducing oxidative damage. These results suggest that PINK1 deficiency exacerbates FSK-induced tau pathology, synaptic damage, mitochondrial dysfunction, and antioxidant system defects, which were reversed by PINK1 overexpression. Our data support a critical role of PINK1-mediated mitophagy in controlling mitochondrial quality, tau hyperphosphorylation, and oxidative stress in a rat model of Alzheimer's disease.

Keywords:  Alzheimer’s disease; Forskolin; Nrf2 signaling; PI3K/Akt/GSK3β signaling; PINK1; Tau hyperphosphorylation; mitophagy; oxidative stress

DOI:  https://doi.org/10.1038/s41401-021-00810-5
J Cell Sci. 2021 Dec 06. pii: jcs.257808. [Epub ahead of print]

MITOL-mediated DRP1 ubiquitylation and degradation promotes mitochondrial hyperfusion in CMT2A-linked MFN2 mutant.

Rajdeep Das, Izaz Monir Kamal, Subhrangshu Das, Saikat Chakrabarti, Oishee Chakrabarti.

  Mutations in Mitofusin2 (MFN2), associated with the pathology of the debilitating neuropathy, Charcot-Marie-Tooth type 2A (CMT2A) are known to alter mitochondrial morphology. One such abundant MFN2 mutant, R364W results in the generation of elongated, interconnected mitochondria. However, the mechanism leading to this mitochondrial aberration remains poorly understood. Here we show that mitochondrial hyperfusion in the presence of R364W-MFN2 is due to increased degradation of DRP1. The Ubiquitin E3 ligase MITOL is known to ubiquitylate both MFN2 and DRP1. Interaction with and its subsequent ubiquitylation by MITOL is stronger in presence of WT-MFN2 than R364W-MFN2. This differential interaction of MITOL with MFN2 in the presence of R364W-MFN2 renders the ligase more available for DRP1 ubiquitylation. Multimonoubiquitylation and proteasomal degradation of DRP1 in R364W-MFN2 cells in the presence of MITOL eventually leads to mitochondrial hyperfusion. Here we provide a mechanistic insight into mitochondrial hyperfusion, while also reporting that MFN2 can indirectly modulate DRP1 - an effect not shown before.

Keywords:  CMT2A-linked MFN2 mutant; DRP1; MITOL; Mitochondrial hyperfusion; Ubiquitylation

DOI:  https://doi.org/10.1242/jcs.257808
Neurobiol Dis. 2021 Dec 07. pii: S0969-9961(21)00331-4. [Epub ahead of print] 105582

Regulation of neuronal autophagy and the implications in neurodegenerative diseases.

Qian Cai, Dhasarathan Ganesan.

  Neurons are highly polarized and post-mitotic cells with the specific requirements of neurotransmission accompanied by high metabolic demands that create a unique challenge for the maintenance of cellular homeostasis. Thus, neurons rely heavily on autophagy that constitutes a key quality control system by which dysfunctional cytoplasmic components, protein aggregates, and damaged organelles are delivered to the lysosome for degradation. While mature lysosomes are predominantly located in the soma of neurons, the robust, constitutive biogenesis of autophagosomes occurs in the synaptic terminal via a conserved pathway that is required to maintain synaptic integrity and function. Following formation, autophagosomes fuse with late endosomes and then are rapidly and efficiently transported by the microtubule-based cytoplasmic dynein motor along the axon toward the soma for lysosomal clearance. In this review, we highlight the recent knowledge of the roles of autophagy in neuronal health and disease. We summarize the available evidence about the normal functions of autophagy as a protective factor against neurodegeneration and discuss the mechanism underlying neuronal autophagy regulation. Finally, we describe how autophagy function is affected in major neurodegenerative diseases with a special focus on Alzheimer's disease, Parkinson's disease, and Amyotrophic Lateral Sclerosis.

Keywords:  Alzheimer's disease; Amphisome; Amyotrophic lateral sclerosis; Autophagosome; Autophagy; Axonal transport; Lysosome; Mitophagy; Parkinson's disease; Synaptic autophagy

DOI:  https://doi.org/10.1016/j.nbd.2021.105582
Front Neurosci. 2021 ;15 784987

The Role of Mitochondria in Optic Atrophy With Autosomal Inheritance.

Elin L Strachan, Delphi Mac White-Begg, John Crean, Alison L Reynolds, Breandán N Kennedy, Niamh C O'Sullivan.

  Optic atrophy (OA) with autosomal inheritance is a form of optic neuropathy characterized by the progressive and irreversible loss of vision. In some cases, this is accompanied by additional, typically neurological, extra-ocular symptoms. Underlying the loss of vision is the specific degeneration of the retinal ganglion cells (RGCs) which form the optic nerve. Whilst autosomal OA is genetically heterogenous, all currently identified causative genes appear to be associated with mitochondrial organization and function. However, it is unclear why RGCs are particularly vulnerable to mitochondrial aberration. Despite the relatively high prevalence of this disorder, there are currently no approved treatments. Combined with the lack of knowledge concerning the mechanisms through which aberrant mitochondrial function leads to RGC death, there remains a clear need for further research to identify the underlying mechanisms and develop treatments for this condition. This review summarizes the genes known to be causative of autosomal OA and the mitochondrial dysfunction caused by pathogenic mutations. Furthermore, we discuss the suitability of available in vivo models for autosomal OA with regards to both treatment development and furthering the understanding of autosomal OA pathology.

Keywords:  in vivo models; mitochondria; optic atrophy; retinal ganglion cells (RGC); retinal organoids

DOI:  https://doi.org/10.3389/fnins.2021.784987
J Vis Exp. 2021 Nov 16.

Live-imaging of Mitochondrial System in Cultured Astrocytes.

Jeanne Espourteille, Valentin Zufferey, Jean-Honoré Laurent, Kevin Richetin.

While much attention has been given to mitochondrial alterations at the neuronal level, recent evidence demonstrates that mitochondrial dynamics and function in astrocytes are implicated in cognition. This article describes the method for time-lapse imaging of astrocyte cultures equipped with a mitochondrial biosensor: MitoTimer. MitoTimer is a powerful and unique tool to assess mitochondrial dynamics, mobility, morphology, biogenesis, and redox state. Here, the different procedures for culture, image acquisitions, and subsequent mitochondrial analysis are presented.

DOI: https://doi.org/10.3791/62957
Int J Mol Sci. 2021 Dec 02. pii: 13059. [Epub ahead of print]22(23):

Mitochondrial Biogenesis in Neurons: How and Where.

Carlos Cardanho-Ramos, Vanessa Alexandra Morais.

  Neurons rely mostly on mitochondria for the production of ATP and Ca2+ homeostasis. As sub-compartmentalized cells, they have different pools of mitochondria in each compartment that are maintained by a constant mitochondrial turnover. It is assumed that most mitochondria are generated in the cell body and then travel to the synapse to exert their functions. Once damaged, mitochondria have to travel back to the cell body for degradation. However, in long cells, like motor neurons, this constant travel back and forth is not an energetically favourable process, thus mitochondrial biogenesis must also occur at the periphery. Ca2+ and ATP levels are the main triggers for mitochondrial biogenesis in the cell body, in a mechanism dependent on the Peroxisome-proliferator-activated γ co-activator-1α-nuclear respiration factors 1 and 2-mitochondrial transcription factor A (PGC-1α-NRF-1/2-TFAM) pathway. However, even though of extreme importance, very little is known about the mechanisms promoting mitochondrial biogenesis away from the cell body. In this review, we bring forward the evoked mechanisms that are at play for mitochondrial biogenesis in the cell body and periphery. Moreover, we postulate that mitochondrial biogenesis may vary locally within the same neuron, and we build upon the hypotheses that, in the periphery, local protein synthesis is responsible for giving all the machinery required for mitochondria to replicate themselves.

Keywords:  NRF-1/2; PGC-1α; TFAM; cell body; mitochondrial biogenesis; neurodegenerative diseases; neurons; periphery

DOI:  https://doi.org/10.3390/ijms222313059
Front Psychiatry. 2021 ;12 737389

Mitochondria-Related Nuclear Gene Expression in the Nucleus Accumbens and Blood Mitochondrial Copy Number After Developmental Fentanyl Exposure in Adolescent Male and Female C57BL/6 Mice.

Cali A Calarco, Megan E Fox, Saskia Van Terheyden, Makeda D Turner, Jason B Alipio, Ramesh Chandra, Mary Kay Lobo.

  The potency of the synthetic opioid fentanyl and its increased clinical availability has led to the rapid escalation of use in the general population, increased recreational exposure, and subsequently opioid-related overdoses. The wide-spread use of fentanyl has, consequently, increased the incidence of in utero exposure to the drug, but the long-term effects of this type of developmental exposure are not yet understood. Opioid use has also been linked to reduced mitochondrial copy number in blood in clinical populations, but the link between this peripheral biomarker and genetic or functional changes in reward-related brain circuitry is still unclear. Additionally, mitochondrial-related gene expression in reward-related brain regions has not been examined in the context of fentanyl exposure, despite the growing literature demonstrating drugs of abuse impact mitochondrial function, which subsequently impacts neuronal signaling. The current study uses exposure to fentanyl via dam access to fentanyl drinking water during gestation and lactation as a model for developmental drug exposure. This perinatal drug-exposure is sufficient to impact mitochondrial copy number in circulating blood leukocytes, as well as mitochondrial-related gene expression in the nucleus accumbens (NAc), a reward-related brain structure, in a sex-dependent manner in adolescent offspring. Specific NAc gene expression is correlated with both blood mitochondrial copy number and with anxiety related behaviors dependent on developmental exposure to fentanyl and sex. These data indicate that developmental fentanyl exposure impacts mitochondrial function in both the brain and body in ways that can impact neuronal signaling and may prime the brain for altered reward-related behavior in adolescence and later into adulthood.

Keywords:  developmental drug exposure; fentanyl; gene expression; mitochondria; mitochondrial copy number; nucleus accumbens

DOI:  https://doi.org/10.3389/fpsyt.2021.737389