Mitochondria manufacture the chemical energy store molecule adenosine triphosphate needed to power biochemical processes. They are the distant descendants of ancient symbiotic bacteria, hundreds of mitochondria found in each cell. Mitochondrial function declines with age for a range of complex reasons involving damage, changes in gene expression that affect mitochondrial proteins, and dysfunction in the quality control mechanisms of mitophagy, processes that should promptly remove damaged mitochondria but falter with age. A variety of approaches to improving mitochondrial function in aged tissue have been proposed, but none of the readily available methods can much improve on the effects of exercise.
Today's research materials discuss a novel approach to coercing mitochondria in aged tissues into better performance. Researchers have produced a proof of concept demonstration in mouse models of neurodegenerative disease, showing improved cognitive function following treatment. In brief, researchers have found that forms of G protein-coupled receptors found on mitochondrial membranes can be stimulated to improve mitochondrial function via their interactions with G proteins inside mitochondria. They designed an artificial receptor that can be stimulated in a controlled way by delivery of a small molecule drug, and used mice equipped with this receptor to dial up mitochondrial function and thus reduce age-related dysfunction in tissues.
Since mitochondrial transplantation is an approach under development for the treatment of age-related disease, it is easy to imagine a future in which cultured mitochondria are engineered in various ways prior to transplantation. Artificial receptors on those mitochondrial that allow for boosted mitochondrial function on demand, in response to ingesting a safe drug, may well be one of the more useful of the many possible enhancements to possess.
Neurodegenerative diseases: What if the key lies in the mitochondria?
Neurodegenerative diseases are characterized by a progressive impairment of neuronal functions leading to the death of brain cells. Researchers developed for the first time a tool that allows to temporarily stimulate mitochondrial activity. They hypothesized that if this stimulation led to an improvement of symptoms in animals, this would mean that the impairment of mitochondrial activity precedes the loss of neurons in the context of a neurodegenerative disease.
In previous studies, the research teams already described the specific role of G proteins in the modulation of mitochondrial activity in the brain. In the present paper, the researchers succeeded in generating an artificial receptor, called mitoDreadd-Gs, able to activate G proteins directly in the mitochondria, thereby stimulating mitochondrial activity. The stimulation of mitoDreadd-Gs in the brain led to the normalisation of both mitochondrial activity and memory performance of dementia mouse models.
Many brain disorders involve mitochondrial alterations, but owing to the lack of suitable tools, the causal role of mitochondrial dysfunction in pathophysiological processes is difficult to establish. Heterotrimeric guanine nucleotide-binding (G) proteins are key regulators of cell functions, and they can be found within mitochondria. Therefore, we reasoned that the activation of stimulatory mitochondrial G proteins (Gs) could rapidly promote the activity of the organelle and possibly compensate for bioenergetic dysfunction.
Here, we show that a mitochondria-targeted recombinant designer receptor exclusively activated by designer drugs (mitoDREADD-Gs) can acutely trigger intramitochondrial signaling to increase mitochondrial membrane potential and oxygen consumption. In vivo activation of mitoDREADD-Gs abolished memory alterations in cannabinoid-treated mice and in two mouse models of Alzheimer's disease and frontotemporal dementia. Thus, mitoDREADD-Gs enables the establishment of causal relationships between mitochondria and biological or disease-related processes and represents an innovative potential therapeutic approach for disorders associated with mitochondrial impairment.
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