bims-midbra 2022-03-27 papers

bims-midbra

Biomed News

on Mitochondrial dynamics in brain cells

Issue of 2022–03–27
six papers selected by
Ana Paula Mendonça, University of Padova

Predicting Mitochondrial Dynamic Behavior in Genetically Defined Neurodegenerative Diseases.
Mitochondrial Phenotypes in Genetically Diverse Neurodegenerative Diseases and Their Response to Mitofusin Activation.
Dusp26 phosphatase regulates mitochondrial respiration and oxidative stress and protects neuronal cell death.
Mitochondrial dynamics in the neonatal brain - a potential target following injury?
Mechanistic Insights of Mitochondrial Dysfunction in Amyotrophic Lateral Sclerosis: An Update on a Lasting Relationship.
Neurons Release Injured Mitochondria as "Help-Me" Signaling After Ischemic Stroke.

Cells. 2022 Mar 19. pii: 1049. [Epub ahead of print]11(6):

Predicting Mitochondrial Dynamic Behavior in Genetically Defined Neurodegenerative Diseases.

Gerald W Dorn, Xiawei Dang.

  Mitochondrial dynamics encompass mitochondrial fusion, fission, and movement. Mitochondrial fission and fusion are seemingly ubiquitous, whereas mitochondrial movement is especially important for organelle transport through neuronal axons. Here, we review the roles of different mitochondrial dynamic processes in mitochondrial quantity and quality control, emphasizing their impact on the neurological system in Charcot-Marie-Tooth disease type 2A, amyotrophic lateral sclerosis, Friedrich's ataxia, dominant optic atrophy, and Alzheimer's, Huntington's, and Parkinson's diseases. In addition to mechanisms and concepts, we explore in detail different technical approaches for measuring mitochondrial dynamic dysfunction in vitro, describe how results from tissue culture studies may be applied to a better understanding of mitochondrial dysdynamism in human neurodegenerative diseases, and suggest how this experimental platform can be used to evaluate candidate therapeutics in different diseases or in individual patients sharing the same clinical diagnosis.

Keywords:  mitochondrial dynamics; mitofusin; neurodegenerative diseases

DOI:  https://doi.org/10.3390/cells11061049
Cells. 2022 Mar 21. pii: 1053. [Epub ahead of print]11(6):

Mitochondrial Phenotypes in Genetically Diverse Neurodegenerative Diseases and Their Response to Mitofusin Activation.

Xiawei Dang, Emily K Walton, Barbara Zablocka, Robert H Baloh, Michael E Shy, Gerald W Dorn.

  Mitochondrial fusion is essential to mitochondrial fitness and cellular health. Neurons of patients with genetic neurodegenerative diseases often exhibit mitochondrial fragmentation, reflecting an imbalance in mitochondrial fusion and fission (mitochondrial dysdynamism). Charcot-Marie-Tooth (CMT) disease type 2A is the prototypical disorder of impaired mitochondrial fusion caused by mutations in the fusion protein mitofusin (MFN)2. Yet, cultured CMT2A patient fibroblast mitochondria are often reported as morphologically normal. Metabolic stress might evoke pathological mitochondrial phenotypes in cultured patient fibroblasts, providing a platform for the pre-clinical individualized evaluation of investigational therapeutics. Here, substitution of galactose for glucose in culture media was used to redirect CMT2A patient fibroblasts (MFN2 T105M, R274W, H361Y, R364W) from glycolytic metabolism to mitochondrial oxidative phosphorylation, which provoked characteristic mitochondrial fragmentation and depolarization and induced a distinct transcriptional signature. Pharmacological MFN activation of metabolically reprogrammed fibroblasts partially reversed the mitochondrial abnormalities in CMT2A and CMT1 and a subset of Parkinson's and Alzheimer's disease patients, implicating addressable mitochondrial dysdynamism in these illnesses.

Keywords:  mitochondrial dynamics; mitofusin; neurodegenerative diseases

DOI:  https://doi.org/10.3390/cells11061053
Cell Mol Life Sci. 2022 Mar 21. 79(4): 198

Dusp26 phosphatase regulates mitochondrial respiration and oxidative stress and protects neuronal cell death.

Binnur Eroglu, Xiongjie Jin, Sadiki Deane, Bahadır Öztürk, Owen A Ross, Demetrius Moskophidis, Nahid F Mivechi.

  The dual specificity protein phosphatases (Dusps) control dephosphorylation of mitogen-activated protein kinases (MAPKs) as well as other substrates. Here, we report that Dusp26, which is highly expressed in neuroblastoma cells and primary neurons is targeted to the mitochondrial outer membrane via its NH2-terminal mitochondrial targeting sequence. Loss of Dusp26 has a significant impact on mitochondrial function that is associated with increased levels of reactive oxygen species (ROS), reduction in ATP generation, reduction in mitochondria motility and release of mitochondrial HtrA2 protease into the cytoplasm. The mitochondrial dysregulation in dusp26-deficient neuroblastoma cells leads to the inhibition of cell proliferation and cell death. In vivo, Dusp26 is highly expressed in neurons in different brain regions, including cortex and midbrain (MB). Ablation of Dusp26 in mouse model leads to dopaminergic (DA) neuronal cell loss in the substantia nigra par compacta (SNpc), inflammatory response in MB and striatum, and phenotypes that are normally associated with Neurodegenerative diseases. Consistent with the data from our mouse model, Dusp26 expressing cells are significantly reduced in the SNpc of Parkinson's Disease patients. The underlying mechanism of DA neuronal death is that loss of Dusp26 in neurons increases mitochondrial ROS and concurrent activation of MAPK/p38 signaling pathway and inflammatory response. Our results suggest that regulation of mitochondrial-associated protein phosphorylation is essential for the maintenance of mitochondrial homeostasis and dysregulation of this process may contribute to the initiation and development of neurodegenerative diseases.

Keywords:  Dopaminergic neurons; Dusp26; LRRK2; Mouse model; Neurodegeneration; p38

DOI:  https://doi.org/10.1007/s00018-022-04162-z
Biosci Rep. 2022 Mar 31. pii: BSR20211696. [Epub ahead of print]42(3):

Mitochondrial dynamics in the neonatal brain - a potential target following injury?

Adam Jones, Claire Thornton.

  The impact of birth asphyxia and its sequelae, hypoxic-ischaemic (HI) brain injury, is long-lasting and significant, both for the infant and for their family. Treatment options are limited to therapeutic hypothermia, which is not universally successful and is unavailable in low resource settings. The energy deficits that accompany neuronal death following interruption of blood flow to the brain implicate mitochondrial dysfunction. Such HI insults trigger mitochondrial outer membrane permeabilisation leading to release of pro-apoptotic proteins into the cytosol and cell death. More recently, key players in mitochondrial fission and fusion have been identified as targets following HI brain injury. This review aims to provide an introduction to the molecular players and pathways driving mitochondrial dynamics, the regulation of these pathways and how they are altered following HI insult. Finally, we review progress on repurposing or repositioning drugs already approved for other indications, which may target mitochondrial dynamics and provide promising avenues for intervention following brain injury. Such repurposing may provide a mechanism to fast-track, low-cost treatment options to the clinic.

Keywords:  cell death; hypoxia; ischaemia-reperfusion injury; mitochondrial dynamics; neonatal

DOI:  https://doi.org/10.1042/BSR20211696
Metabolites. 2022 Mar 09. pii: 233. [Epub ahead of print]12(3):

Mechanistic Insights of Mitochondrial Dysfunction in Amyotrophic Lateral Sclerosis: An Update on a Lasting Relationship.

Niccolò Candelise, Illari Salvatori, Silvia Scaricamazza, Valentina Nesci, Henri Zenuni, Alberto Ferri, Cristiana Valle.

  Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive loss of the upper and lower motor neurons. Despite the increasing effort in understanding the etiopathology of ALS, it still remains an obscure disease, and no therapies are currently available to halt its progression. Following the discovery of the first gene associated with familial forms of ALS, Cu-Zn superoxide dismutase, it appeared evident that mitochondria were key elements in the onset of the pathology. However, as more and more ALS-related genes were discovered, the attention shifted from mitochondria impairment to other biological functions such as protein aggregation and RNA metabolism. In recent years, mitochondria have again earned central, mechanistic roles in the pathology, due to accumulating evidence of their derangement in ALS animal models and patients, often resulting in the dysregulation of the energetic metabolism. In this review, we first provide an update of the last lustrum on the molecular mechanisms by which the most well-known ALS-related proteins affect mitochondrial functions and cellular bioenergetics. Next, we focus on evidence gathered from human specimens and advance the concept of a cellular-specific mitochondrial "metabolic threshold", which may appear pivotal in ALS pathogenesis.

Keywords:  amyotrophic lateral sclerosis; bioenergetic; metabolism; mitochondria; motor neuron disease

DOI:  https://doi.org/10.3390/metabo12030233
Front Aging Neurosci. 2022 ;14 785761

Neurons Release Injured Mitochondria as "Help-Me" Signaling After Ischemic Stroke.

Li Gao, Fan Liu, Pin-Pin Hou, Anatol Manaenko, Zhi-Peng Xiao, Fei Wang, Tian-Le Xu, Qin Hu.

  Mitochondrial dysfunction has been regarded as one of the major contributors of ischemic neuronal death after stroke. Recently, intercellular mitochondrial transfer between different cell types has been widely studied and suggested as a potential therapeutic approach. However, whether mitochondria are involved in the neuron-glia cross-talk following ischemic stroke and the underlying mechanisms have not been explored yet. In this study, we demonstrated that under physiological condition, neurons release few mitochondria into the extracellular space, and the mitochondrial release increased when subjected to the challenges of acidosis, hydrogen peroxide (H2O2), N-methyl-D-aspartate (NMDA), or glutamate. Acidosis reduced the mitochondrial basal respiration and lowered the membrane potential in primary-cultured mouse cortical neurons. These defective mitochondria were prone to be expelled to the extracellular space by the injured neurons, and were engulfed by adjacent astrocytes, leading to increased astrocytic expressions of mitochondrial Rho GTPase 1 (Miro 1) and mitochondrial transcription factor A (TFAM) at mRNA level. In mice subjected to transient focal cerebral ischemia, the number of defective mitochondria in the cerebrospinal fluid increased. Our results suggested that the neuron-derived mitochondria may serve as a "help-me" signaling and mediate the neuron-astrocyte cross-talk following ischemic stroke. Promoting the intercellular mitochondrial transfer by accelerating the neuronal releasing or astrocytic engulfing might be a potential and attractive therapeutic strategy for the treatment of ischemic stroke in the future.

Keywords:  ischemic stroke; metabolic stress; mitochondrial biogenesis; mitochondrial release; neuron-glial crosstalk

DOI:  https://doi.org/10.3389/fnagi.2022.785761