Mitochondria and astrocyte reactivity: Key mechanism behind neuronal injury

Neuroscience 2025 Feb 16:567:227-234

Patricia Cassina 1 , Ernesto Miquel 2 , Laura Martínez-Palma 2 , Adriana Cassina 3

1 Departamento de Histología y Embriología, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay. Electronic address: pcassina@fmed.edu.uy. 2 Departamento de Histología y Embriología, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay. 3 Departemento de Bioquímica and Centro de Investigaciones Biomédicas (CEINBIO), Facultad de Medicina, Universidad de la República, Montevideo, Uruguay.

DOI: 10.1016/j.neuroscience.2024.12.058
PMID: 39788313
Pubmed: https://pubmed.ncbi.nlm.nih.gov/39788313
Texto completo: https://linkinghub.elsevier.com/retrieve/pii/S0306-4522(24)00765-6

Abstract:
In this special issue to celebrate the 30th anniversary of the Uruguayan Society for Neuroscience (SNU), we find it pertinent to highlight that research on glial cells in Uruguay began almost alongside the history of SNU and contributed to the understanding of neuron-glia interactions within the international scientific community. Glial cells, particularly astrocytes, traditionally regarded as supportive components in the central nervous system (CNS), undergo notable morphological and functional alterations in response to neuronal damage, a phenomenon referred to as glial reactivity. Among the myriad functions of astrocytes, metabolic support holds significant relevance for neuronal function, given the high energy demand of the nervous system. Although astrocytes are typically considered to exhibit low mitochondrial respiratory chain activity, they possess a noteworthy mitochondrial network. Interestingly, both the morphology and activity of these organelles change following glial reactivity. Despite receiving less attention compared to studies on neuronal mitochondria, recent studies indicate that mitochondria play a crucial role in driving the transition of astrocytes from a quiescent to a reactive state in various neurological disorders. Notably, stimulating mitochondria in astrocytes has been shown to reduce damage associated with the neurodegenerative disease amyotrophic lateral sclerosis. Here, we focus on studies supporting the emerging paradigm that metabolic reprogramming occurs in astrocytes following damage, which is associated with their phenotypic shift to a new functional state that significantly influences the progression of pathology. Thus, exploring mitochondrial activity and metabolic reprogramming within glial cells may provide valuable insights for developing innovative therapeutic approaches to mitigate neuronal damage. In this review, we focus on studies supporting the emerging paradigm that metabolic reprogramming occurs in astrocytes following damage, which is associated with their phenotypic shift to a new functional state that significantly influences the progression of pathology. Thus, exploring mitochondrial activity and metabolic reprogramming within glial cells may provide valuable insights for developing innovative therapeutic approaches to mitigate neuronal damage.

2025_Cassina_rev_Mitochondria and astrocyte reactivity-Key mechanism behind neuronal injury.pdf

Evaluation of the efficacy and safety of gravitational therapy in a cohort of patients with systemic sclerosis

Reumatol Clin 2024 Nov;20(9):463-469

Luisa Fernanda Servioli 1 , Eugenia Isasi 2 , Alejandra Pérez 3 , Silvia Pouquette 3 , María Eloísa Isasi 3

1 Unidad de Enfermedades Autoinmunes Sistémicas, Hospital Militar, Montevideo, Uruguay. Electronic address: lservioli01@gmail.com. 2 Unidad Académica de Histología y Embriología, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay; Centro de Terapia Gravitacional, Montevideo, Uruguay. 3 Centro de Terapia Gravitacional, Montevideo, Uruguay.

DOI: 10.1016/j.reumae.2024.10.004
PMID: 39487058
Pubmed: https://pubmed.ncbi.nlm.nih.gov/39487058
Texto completo: http://www.elsevier.es/en/linksolver/pdf/pii/S2173-5743(24)00137-0

Abstract:
Background: The exposure to artificial gravity (AG) through human centrifugation is the basis of the treatment called gravity therapy (GT), in which the mechanical stimulation over the vessel wall, induces the synthesis and release of prostacyclin. It has been used for more than four decades in Uruguay in the treatment of different vascular-based pathologies. In patients with systemic sclerosis (SSc) it has shown good benefits and excellent safety profile over the years. However, there is a lack of knowledge in the scientific community about GT and its results.

Cerebral White Matter Alterations Associated With Oligodendrocyte Vulnerability in Organic Acidurias: Insights in Glutaric Aciduria Type I

Neurotox Res 2024 Jul 4;42(4):33

Eugenia Isasi 1 2 , Moacir Wajner 3 4 , Juliana Avila Duarte 5 , Silvia Olivera-Bravo 6

1 Laboratorio de Neurobiología Celular y Molecular, Unidad Académica de Histología y Embriología, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay. 2 Departamento de Neurobiología y Neuropatología, Instituto de Investigaciones Biológicas Clemente Estable (IIBCE), Montevideo, Uruguay. 3 Department of Biochemistry, Instituto de Ciencias Básicas da Saude, Universidade Federal de Río Grande do Sul, Porto Alegre, Brazil. 4 Medical Genetics Service, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil. 5 Departamento de Medicina Interna, Serviço de Radiología, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil. 6 Departamento de Neurobiología y Neuropatología, Instituto de Investigaciones Biológicas Clemente Estable (IIBCE), Montevideo, Uruguay. solivera@iibce.edu.uy.

DOI: 10.1007/s12640-024-00710-6
PMID: 38963434
Pubmed: https://pubmed.ncbi.nlm.nih.gov/38963434
Texto completo: https://dx.doi.org/10.1007/s12640-024-00710-6

Abstract:
The white matter is an important constituent of the central nervous system, containing axons, oligodendrocytes, and its progenitor cells, astrocytes, and microglial cells. Oligodendrocytes are central for myelin synthesis, the insulating envelope that protects axons and allows normal neural conduction. Both, oligodendrocytes and myelin, are highly vulnerable to toxic factors in many neurodevelopmental and neurodegenerative disorders associated with disturbances of myelination. Here we review the main alterations in oligodendrocytes and myelin observed in some organic acidurias/acidemias, which correspond to inherited neurometabolic disorders biochemically characterized by accumulation of potentially neurotoxic organic acids and their derivatives. The yet incompletely understood mechanisms underlying the high vulnerability of OLs and/or myelin in glutaric acidemia type I, the most prototypical cerebral organic aciduria, are particularly discussed.

Pyruvate dehydrogenase kinase 2 knockdown restores the ability of amyotrophic lateral sclerosis-linked SOD1G93A rat astrocytes to support motor neuron survival by increasing mitochondrial respiration

Glia 2024 May;72(5):999-1011

Ernesto Miquel 1 , Rosalía Villarino 1 , Laura Martínez-Palma 1 , Adriana Cassina 2 , Patricia Cassina 1

1 Departamento de Histología y Embriología, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay. 2 Departamento de Bioquímica, Centro de Investigaciones Biomédicas (CEINBIO), Facultad de Medicina, Universidad de la República, Montevideo, Uruguay.

DOI: 10.1002/glia.24516
PMID: 38372421
Pubmed: https://pubmed.ncbi.nlm.nih.gov/38372421
Texto completo: https://doi.org/10.1002/glia.24516

Abstract:
Amyotrophic lateral sclerosis (ALS) is characterized by progressive motor neuron (MN) degeneration. Various studies using cellular and animal models of ALS indicate that there is a complex interplay between MN and neighboring non-neuronal cells, such as astrocytes, resulting in noncell autonomous neurodegeneration. Astrocytes in ALS exhibit a lower ability to support MN survival than nondisease-associated ones, which is strongly correlated with low-mitochondrial respiratory activity. Indeed, pharmacological inhibition of pyruvate dehydrogenase kinase (PDK) led to an increase in the mitochondrial oxidative phosphorylation pathway as the primary source of cell energy in SOD1G93A astrocytes and restored the survival of MN. Among the four PDK isoforms, PDK2 is ubiquitously expressed in astrocytes and presents low expression levels in neurons. Herein, we hypothesize whether selective knockdown of PDK2 in astrocytes may increase mitochondrial activity and, in turn, reduce SOD1G93A-associated toxicity. To assess this, cultured neonatal SOD1G93A rat astrocytes were incubated with specific PDK2 siRNA. This treatment resulted in a reduction of the enzyme expression with a concomitant decrease in the phosphorylation rate of the pyruvate dehydrogenase complex. In addition, PDK2-silenced SOD1G93A astrocytes exhibited restored mitochondrial bioenergetics parameters, adopting a more complex mitochondrial network. This treatment also decreased lipid droplet content in SOD1G93A astrocytes, suggesting a switch in energetic metabolism. Significantly, PDK2 knockdown increased the ability of SOD1G93A astrocytes to support MN survival, further supporting the major role of astrocyte mitochondrial respiratory activity in astrocyte-MN interactions. These results suggest that PDK2 silencing could be a cell-specific therapeutic tool to slow the progression of ALS.

Miquel_2024_Pyruvate dehydrogenase kinase 2 knockdown astrocytes ALS.pdf