bims-midbra 2022-01-23 papers

bims-midbra

Biomed News

on Mitochondrial dynamics in brain cells

Issue of 2022‒01‒23
eight papers selected by
Ana Paula Mendonça
University of Padova

Mechanisms associated with the dysregulation of mitochondrial function due to lead exposure and possible implications on the development of Alzheimer's disease.
Brain-derived autophagosome profiling reveals the engulfment of nucleoid-enriched mitochondrial fragments by basal autophagy in neurons.
OPA1 Modulates Mitochondrial Ca2+ Uptake Through ER-Mitochondria Coupling.
A New Insight into an Alternative Therapeutic Approach to Restore Redox Homeostasis and Functional Mitochondria in Neurodegenerative Diseases.
Therapeutic Strategies Targeting Mitochondrial Calcium Signaling: A New Hope for Neurological Diseases?
Disrupted Mitochondrial Network Drives Deficits of Learning and Memory in a Mouse Model of FOXP1 Haploinsufficiency.
Selective localization of Mfn2 near PINK1 enables its preferential ubiquitination by Parkin on mitochondria.
PINK1 Alleviates Cognitive Impairments via Attenuating Pathological Tau Aggregation in a Mouse Model of Tauopathy.

Biometals. 2022 Jan 20.

Mechanisms associated with the dysregulation of mitochondrial function due to lead exposure and possible implications on the development of Alzheimer's disease.

Lakshmi Jaya Madhuri Bandaru, Neelima Ayyalasomayajula, Lokesh Murumulla, Suresh Challa.

  Lead (Pb) is a multimedia contaminant with various pathophysiological consequences, including cognitive decline and neural abnormalities. Recent findings have reported an association of Pb toxicity with Alzheimer's disease (AD). Studies have revealed that mitochondrial dysfunction is a pathological characteristic of AD. According to toxicology reports, Pb promotes mitochondrial oxidative stress by lowering complex III activity in the electron transport chain, boosting reactive oxygen species formation, and reducing the cell's antioxidant defence system. Here, we review recent advances in the role of mitochondria in Pb-induced AD pathology, as well as the mechanisms associated with the mitochondrial dysfunction, such as the depolarisation of the mitochondrial membrane potential, mitochondrial permeability transition pore opening; mitochondrial biogenesis, bioenergetics and mitochondrial dynamics alterations; and mitophagy and apoptosis. We also discuss possible therapeutic options for mitochondrial-targeted neurodegenerative disease (AD).

Keywords:  Alzheimer’s disease; Lead toxicity; Mitochondrial dysfunction; Reactive oxygen species; β-Amyloid peptide

DOI:  https://doi.org/10.1007/s10534-021-00360-7
Neuron. 2022 Jan 13. pii: S0896-6273(21)01046-1. [Epub ahead of print]

Brain-derived autophagosome profiling reveals the engulfment of nucleoid-enriched mitochondrial fragments by basal autophagy in neurons.

Juliet Goldsmith, Alban Ordureau, J Wade Harper, Erika L F Holzbaur.

  Neurons depend on autophagy to maintain cellular homeostasis, and defects in autophagy are pathological hallmarks of neurodegenerative disease. To probe the role of basal autophagy in the maintenance of neuronal health, we isolated autophagic vesicles from mouse brain tissue and used proteomics to identify the major cargos engulfed within autophagosomes, validating our findings in rodent primary and human iPSC-derived neurons. Mitochondrial proteins were identified as a major cargo in the absence of mitophagy adaptors such as OPTN. We found that nucleoid-associated proteins are enriched compared with other mitochondrial components. In the axon, autophagic engulfment of nucleoid-enriched mitochondrial fragments requires the mitochondrial fission machinery Drp1. We proposed that localized Drp1-dependent fission of nucleoid-enriched fragments in proximity to the sites of autophagosome biogenesis enhances their capture. The resulting efficient autophagic turnover of nucleoids may prevent accumulation of mitochondrial DNA in the neuron, thus mitigating activation of proinflammatory pathways that contribute to neurodegeneration.

Keywords:  Drp1; TFAM; autophagy; mitochondria; mitochondrial division; mitochondrial nucleoids; mitophagy; neurodegeneration; neuronal homeostasis

DOI:  https://doi.org/10.1016/j.neuron.2021.12.029
Front Cell Dev Biol. 2021 ;9 774108

OPA1 Modulates Mitochondrial Ca2+ Uptake Through ER-Mitochondria Coupling.

Benjamín Cartes-Saavedra, Josefa Macuada, Daniel Lagos, Duxan Arancibia, María E Andrés, Patrick Yu-Wai-Man, György Hajnóczky, Verónica Eisner.

  Autosomal Dominant Optic Atrophy (ADOA), a disease that causes blindness and other neurological disorders, is linked to OPA1 mutations. OPA1, dependent on its GTPase and GED domains, governs inner mitochondrial membrane (IMM) fusion and cristae organization, which are central to oxidative metabolism. Mitochondrial dynamics and IMM organization have also been implicated in Ca2+ homeostasis and signaling but the specific involvements of OPA1 in Ca2+ dynamics remain to be established. Here we studied the possible outcomes of OPA1 and its ADOA-linked mutations in Ca2+ homeostasis using rescue and overexpression strategies in Opa1-deficient and wild-type murine embryonic fibroblasts (MEFs), respectively and in human ADOA-derived fibroblasts. MEFs lacking Opa1 required less Ca2+ mobilization from the endoplasmic reticulum (ER) to induce a mitochondrial matrix [Ca2+] rise ([Ca2+]mito). This was associated with closer ER-mitochondria contacts and no significant changes in the mitochondrial calcium uniporter complex. Patient cells carrying OPA1 GTPase or GED domain mutations also exhibited altered Ca2+ homeostasis, and the mutations associated with lower OPA1 levels displayed closer ER-mitochondria gaps. Furthermore, in Opa1 -/- MEF background, we found that acute expression of OPA1 GTPase mutants but no GED mutants, partially restored cytosolic [Ca2+] ([Ca2+]cyto) needed for a prompt [Ca2+]mito rise. Finally, OPA1 mutants' overexpression in WT MEFs disrupted Ca2+ homeostasis, partially recapitulating the observations in ADOA patient cells. Thus, OPA1 modulates functional ER-mitochondria coupling likely through the OPA1 GED domain in Opa1 -/- MEFs. However, the co-existence of WT and mutant forms of OPA1 in patients promotes an imbalance of Ca2+ homeostasis without a domain-specific effect, likely contributing to the overall ADOA progress.

Keywords:  ADOA; OPA1; calcium; endoplasmic reticulum; mitochondria

DOI:  https://doi.org/10.3389/fcell.2021.774108
Antioxidants (Basel). 2021 Dec 21. pii: 7. [Epub ahead of print]11(1):

A New Insight into an Alternative Therapeutic Approach to Restore Redox Homeostasis and Functional Mitochondria in Neurodegenerative Diseases.

Dong-Hoon Hyun, Jaewang Lee.

  Neurodegenerative diseases are accompanied by oxidative stress and mitochondrial dysfunction, leading to a progressive loss of neuronal cells, formation of protein aggregates, and a decrease in cognitive or motor functions. Mitochondrial dysfunction occurs at the early stage of neurodegenerative diseases. Protein aggregates containing oxidatively damaged biomolecules and other misfolded proteins and neuroinflammation have been identified in animal models and patients with neurodegenerative diseases. A variety of neurodegenerative diseases commonly exhibits decreased activity of antioxidant enzymes, lower amounts of antioxidants, and altered cellular signalling. Although several molecules have been approved clinically, there is no known cure for neurodegenerative diseases, though some drugs are focused on improving mitochondrial function. Mitochondrial dysfunction is caused by oxidative damage and impaired cellular signalling, including that of peroxisome proliferator-activated receptor gamma coactivator 1α. Mitochondrial function can also be modulated by mitochondrial biogenesis and the mitochondrial fusion/fission cycle. Mitochondrial biogenesis is regulated mainly by sirtuin 1, NAD+, AMP-activated protein kinase, mammalian target of rapamycin, and peroxisome proliferator-activated receptor γ. Altered mitochondrial dynamics, such as increased fission proteins and decreased fusion products, are shown in neurodegenerative diseases. Due to the restrictions of a target-based approach, a phenotype-based approach has been performed to find novel proteins or pathways. Alternatively, plasma membrane redox enzymes improve mitochondrial function without the further production of reactive oxygen species. In addition, inducers of antioxidant response elements can be useful to induce a series of detoxifying enzymes. Thus, redox homeostasis and metabolic regulation can be important therapeutic targets for delaying the progression of neurodegenerative diseases.

Keywords:  mitochondrial biogenesis; mitochondrial dynamics; mitochondrial dysfunction; neurodegenerative diseases; neuroinflammation; oxidative stress; plasma membrane redox enzymes

DOI:  https://doi.org/10.3390/antiox11010007
Antioxidants (Basel). 2022 Jan 15. pii: 165. [Epub ahead of print]11(1):

Therapeutic Strategies Targeting Mitochondrial Calcium Signaling: A New Hope for Neurological Diseases?

Laura R Rodríguez, Tamara Lapeña-Luzón, Noelia Benetó, Vicent Beltran-Beltran, Federico V Pallardó, Pilar Gonzalez-Cabo, Juan Antonio Navarro.

  Calcium (Ca2+) is a versatile secondary messenger involved in the regulation of a plethora of different signaling pathways for cell maintenance. Specifically, intracellular Ca2+ homeostasis is mainly regulated by the endoplasmic reticulum and the mitochondria, whose Ca2+ exchange is mediated by appositions, termed endoplasmic reticulum-mitochondria-associated membranes (MAMs), formed by proteins resident in both compartments. These tethers are essential to manage the mitochondrial Ca2+ influx that regulates the mitochondrial function of bioenergetics, mitochondrial dynamics, cell death, and oxidative stress. However, alterations of these pathways lead to the development of multiple human diseases, including neurological disorders, such as amyotrophic lateral sclerosis, Friedreich's ataxia, and Charcot-Marie-Tooth. A common hallmark in these disorders is mitochondrial dysfunction, associated with abnormal mitochondrial Ca2+ handling that contributes to neurodegeneration. In this work, we highlight the importance of Ca2+ signaling in mitochondria and how the mechanism of communication in MAMs is pivotal for mitochondrial maintenance and cell homeostasis. Lately, we outstand potential targets located in MAMs by addressing different therapeutic strategies focused on restoring mitochondrial Ca2+ uptake as an emergent approach for neurological diseases.

Keywords:  Charcot–Marie–Tooth; Friedreich’s ataxia; amyotrophic lateral sclerosis; calcium; endoplasmic reticulum; mitochondria; mitochondrial calcium uniporter; neurological; sigma-1 receptor

DOI:  https://doi.org/10.3390/antiox11010165
Genes (Basel). 2022 Jan 11. pii: 127. [Epub ahead of print]13(1):

Disrupted Mitochondrial Network Drives Deficits of Learning and Memory in a Mouse Model of FOXP1 Haploinsufficiency.

Jing Wang, Gudrun A Rappold, Henning Fröhlich.

  Reduced cognitive flexibility, characterized by restricted interests and repetitive behavior, is associated with atypical memory performance in autism spectrum disorder (ASD), suggesting hippocampal dysfunction. FOXP1 syndrome is a neurodevelopmental disorder characterized by ASD, language deficits, global developmental delay, and mild to moderate intellectual disability. Strongly reduced Foxp1 expression has been detected in the hippocampus of Foxp1+/- mice, a brain region required for learning and memory. To investigate learning and memory performance in these animals, fear conditioning tests were carried out, which showed impaired associative learning compared with wild type (WT) animals. To shed light on the underlying mechanism, we analyzed various components of the mitochondrial network in the hippocampus. Several proteins regulating mitochondrial biogenesis (e.g., Foxo1, Pgc-1α, Tfam) and dynamics (Mfn1, Opa1, Drp1 and Fis1) were significantly dysregulated, which may explain the increased mitophagy observed in the Foxp1+/- hippocampus. The reduced activity of complex I and decreased expression of Sod2 most likely increase the production of reactive oxygen species and the expression of the pre-apoptotic proteins Bcl-2 and Bax in this tissue. In conclusion, we provide evidence that a disrupted mitochondrial network and the resulting oxidative stress in the hippocampus contribute to the altered learning and cognitive impairment in Foxp1+/- mice, suggesting that similar alterations also play a major role in patients with FOXP1 syndrome.

Keywords:  FOXP1 syndrome; Foxp1+/− mouse; associative learning; autism spectrum disorder; hippocampus; mitochondrial dysfunction; reactive oxygen species

DOI:  https://doi.org/10.3390/genes13010127
Open Biol. 2022 Jan;12(1): 210255

Selective localization of Mfn2 near PINK1 enables its preferential ubiquitination by Parkin on mitochondria.

Marta Vranas, Yang Lu, Shafqat Rasool, Nathalie Croteau, Jonathan D Krett, Véronique Sauvé, Kalle Gehring, Edward A Fon, Thomas M Durcan, Jean-François Trempe.

  Mutations in Parkin and PINK1 cause early-onset familial Parkinson's disease. Parkin is a RING-In-Between-RING E3 ligase that transfers ubiquitin from an E2 enzyme to a substrate in two steps: (i) thioester intermediate formation on Parkin and (ii) acyl transfer to a substrate lysine. The process is triggered by PINK1, which phosphorylates ubiquitin on damaged mitochondria, which in turn recruits and activates Parkin. This leads to the ubiquitination of outer mitochondrial membrane proteins and clearance of the organelle. While the targets of Parkin on mitochondria are known, the factors determining substrate selectivity remain unclear. To investigate this, we examined how Parkin catalyses ubiquitin transfer to substrates. We found that His433 in the RING2 domain contributes to the catalysis of acyl transfer. In cells, the mutation of His433 impairs mitophagy. In vitro ubiquitination assays with isolated mitochondria show that Mfn2 is a kinetically preferred substrate. Using proximity-ligation assays, we show that Mfn2 specifically co-localizes with PINK1 and phospho-ubiquitin (pUb) in U2OS cells upon mitochondrial depolarization. We propose a model whereby ubiquitination of Mfn2 is efficient by virtue of its localization near PINK1, which leads to the recruitment and activation of Parkin via pUb at these sites.

Keywords:  Mfn2; PINK1; Parkin; mitochondria; ubiquitin

DOI:  https://doi.org/10.1098/rsob.210255
Front Cell Dev Biol. 2021 ;9 736267

PINK1 Alleviates Cognitive Impairments via Attenuating Pathological Tau Aggregation in a Mouse Model of Tauopathy.

Xing Jun Jiang, Yan Qing Wu, Rong Ma, Yan Min Chang, Lu Lu Li, Jia Hui Zhu, Gong Ping Liu, Gang Li.

  As a primary cause of dementia and death in older people, Alzheimer's disease (AD) has become a common problem and challenge worldwide. Abnormal accumulation of tau proteins in the brain is a hallmark pathology of AD and is closely related to the clinical progression and severity of cognitive deficits. Here, we found that overexpression of phosphatase and tensin homolog (PTEN)-induced kinase 1 (PINK1) effectively promoted the degradation of tau, thereby rescuing neuron loss, synaptic damage, and cognitive impairments in a mouse model of tauopathy with AAV-full-length human Tau (hTau) injected into the hippocampal CA1 area (hTau mice). Overexpression of PINK1 activated autophagy, and chloroquine but not MG132 reversed the PINK1-induced decrease in human Tau levels and cognitive improvement in hTau mice. Furthermore, PINK1 also ameliorated mitochondrial dysfunction induced by hTau. Taken together, our data revealed that PINK1 overexpression promoted degradation of abnormal accumulated tau via the autophagy-lysosome pathway, indicating that PINK1 may be a potential target for AD treatment.

Keywords:  Alzheimer’s disease; PINK1; autophagy; memory; tau

DOI:  https://doi.org/10.3389/fcell.2021.736267