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. 2023 Jul;18(7):1486-1488.
doi: 10.4103/1673-5374.360279.

Overcoming mitochondrial dysfunction in neurodegenerative diseases

João Pessoa  1 , Ana I Duarte  1
Affiliations

Overcoming mitochondrial dysfunction in neurodegenerative diseases

João Pessoa et al. Neural Regen Res. 2023 Jul.
No abstract available

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Figures

Figure 1
Figure 1
Strategies to overcome mitochondrial dysfunction in neurodegenerative diseases. (A) Neurodegenerative diseases result from, among other factors, mitochondrial dysfunction. Dysfunctional mitochondria cause not only a shortage in adenosine triphosphate (ATP) but also the excessive accumulation of reactive oxygen species (ROS) and oxidative stress. These alterations are aggravated by the inhibition of autophagy and the consequent failure in removing dysfunctional mitochondria. Accumulation of ROS triggers neural apoptosis. (B) Strategies to deliver drugs into the brain must utilize molecules or molecule vehicles able to cross the blood-brain barrier. A small molecule drug can be engineered to mimic a natural substrate of a small molecule transporter in the membrane of an endothelial cell (represented in blue), allowing it to cross the blood-brain barrier. Exogenous genes coding for therapeutic proteins or peptides can be encapsulated inside liposomes coated with monoclonal antibodies (represented in cyan), which will interact with large molecule transporters (represented in blue). This interaction will drive transcytosis of the exogenous gene through the blood-brain barrier. (C) Once inside neurons, exogenous genes will be imported into the nucleus. Small molecules will exert, e.g., the transcriptional activation of endogenous genes or the up-regulation of glycolysis. Of note, terazosin, an activator of phosphoglycerate kinase 1, may exert neuroprotective effects through the activation of glycolysis, as observed in Parkinson’s disease mice and patients. Transcriptional activation of endogenous or exogenous genes (by RNA polymerases represented in gray in the nucleus) will increase the cellular levels of glucagon-like peptide 1 (GLP-1) receptor agonists (GLP-1RAs), hypoxia-inducible factor 1α (HIF-1α), and peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), ultimately increasing glucose uptake, glycolysis, and mitochondrial biogenesis, respectively. These three cellular processes function to overcome neuronal mitochondrial dysfunction through the up-regulation of ATP-producing pathways. Elements were not drawn to scale.
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