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Published on: May 5, 2022
Neuronal bioenergetics and acute mitochondrial dysfunction: a clue to understanding the central nervous system side
Haryes A Funes1, Nadezda Apostolova2, Fernando Alegre1
1Departamento de Farmacología, Facultad de Medicina FISABIO-Hospital Universitario Dr. Peset.
Background:
Neurological pathogenesis is associated with mitochondrial dysfunction and differences in neuronal/glial handling of oxygen and glucose. The main side effects attributed to efavirenz involve the CNS, but the underlying mechanisms are unclear.
Methods:
Human cell lines and rat primary cultures of neurons and astrocytes were treated with clinically relevant efavirenz concentration.
Results:
Efavirenz alters mitochondrial respiration, enhances reactive oxygen species generation, undermines mitochondrial membrane potential, and reduces adenosine triphosphate (ATP) levels in a concentration-dependent fashion in both neurons and glial cells. However, it activates adenosine monophosphate-activated protein kinase only in glial cells, upregulating glycolysis and increasing intracellular ATP levels, which do not occur in neurons. To reproduce the conditions that often exist in human immunodeficiency virus-related neuroinflammatory disorders, the effects of efavirenz were evaluated in the presence of exogenous nitric oxide, an inflammatory mediator and mitochondrial inhibitor. The combination potentiated the effects on mitochondrial parameters in both neurons and glial cells, but ATP generation and lactate production were enhanced only in glial cells.
Conclusions:
Efavirenz affects the bioenergetics of neurons through a mechanism involving acute mitochondrial inhibition, an action exacerbated in neuroinflammatory conditions. A similar scenario of glial cells survival and degeneration of neurons with signs of mitochondrial dysfunction and oxidative stress has been associated with neurocognitive disorders.
Insights
Efavirenz impairs neuronal energy production by inhibiting mitochondria, especially during neuroinflammation. Glial cells show increased energy production, unlike neurons, potentially contributing to neurocognitive disorders.
Area of Science:
- Neuroscience
- Biochemistry
- Pharmacology
Background:
- Neurological disorders often involve mitochondrial dysfunction and altered cellular metabolism.
- Efavirenz, an antiretroviral drug, has known central nervous system (CNS) side effects with unclear mechanisms.
Purpose of the Study:
- To investigate the effects of efavirenz on neuronal and glial cell bioenergetics.
- To elucidate the mechanisms underlying efavirenz-induced CNS side effects.
Main Methods:
- Human cell lines and rat primary neuronal/glial cultures were exposed to efavirenz.
- Mitochondrial respiration, ATP levels, and glycolysis were assessed.
- Effects were evaluated under basal conditions and in the presence of nitric oxide to mimic neuroinflammation.
Main Results:
- Efavirenz reduced mitochondrial respiration, membrane potential, and ATP levels in both neurons and glial cells.
- Glial cells upregulated glycolysis and increased ATP via AMPK activation, while neurons did not.
- Nitric oxide exacerbated mitochondrial dysfunction but further enhanced ATP and lactate production in glial cells.
Conclusions:
- Efavirenz induces neuronal bioenergetic deficits via mitochondrial inhibition, worsened by neuroinflammation.
- Differential metabolic responses in neurons and glial cells may contribute to efavirenz neurotoxicity and associated cognitive impairments.
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