Key Points
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Over the past decade, more evidence has accumulated regarding the involvement of mitochondrial dysfunction in the pathogenesis of type 2 diabetes, sarcopaenia, Parkinson's disease, cancer and, to a lesser extent, Alzheimer's disease. Modulating mitochondrial function has therefore emerged as an attractive strategy to treat both inherited mitochondrial diseases and age-related diseases associated with mitochondrial dysfunction, and spurred active drug discovery efforts in this area.
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Several pathways are important to maintain and/or restore mitochondrial function and hence have potential therapeutic value. The best-characterized pathway is that involving the regulation of mitochondrial function by sensors of the nutrient or energy status, such as the pathway involving AMP-activated protein kinase (AMPK) and sirtuin 1 (SIRT1) and their downstream effectors. Other key pathways that regulate mitochondrial function, such as fusion and/or fission, mitophagy and the mitochondrial unfolded protein response, have been recently added to the equation, but there are very few compounds available to specifically modulate these pathways.
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Most of the compounds that modulate mitochondrial function have been identified via target-based screens, including compounds that bind to and modulate G-protein-coupled receptors (such as G protein-coupled bile acid receptor 1), nuclear receptors and other transcription factors (such as peroxisome proliferator-activated receptors and oestrogen-related receptors), kinases (such as AMPK) and enzymes (such as SIRT1).
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Recently, several phenotypic screening strategies have enabled the identification of novel chemical entities that modulate more global phenotypes, such as fusion and mitochondrial biogenesis. These kinds of strategies can be a powerful approach for identifying novel pathways or proteins involved in the regulatory network of mitochondrial function.
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By combining the results of several phenotypic tests, it is possible to define a comprehensive set of mitochondrial signatures that enable the clustering of novel chemical entities according to their footprint on mitochondrial function. Such a signature will also help determine the particular mitochondrial signalling pathway that is affected, facilitating downstream target deconvolution.
Abstract
Mitochondrial dysfunction is not only a hallmark of rare inherited mitochondrial disorders but also implicated in age-related diseases, including those that affect the metabolic and nervous system, such as type 2 diabetes and Parkinson's disease. Numerous pathways maintain and/or restore proper mitochondrial function, including mitochondrial biogenesis, mitochondrial dynamics, mitophagy and the mitochondrial unfolded protein response. New and powerful phenotypic assays in cell-based models as well as multicellular organisms have been developed to explore these different aspects of mitochondrial function. Modulating mitochondrial function has therefore emerged as an attractive therapeutic strategy for several diseases, which has spurred active drug discovery efforts in this area.
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Acknowledgements
The authors thank R. Wanders for critically reading the manuscript. R.H.H. is financially supported by an AMC Postdoctoral fellowship and a ZonMw-VENI grant (number 91613050). J.A. is the Nestlé Chair in Energy Metabolism and work in his laboratory is supported by the École polytechnique fédérale de Lausanne (EPFL), the EU Ideas program (ERC-2008-AdG-231138), the US National Institutes of Health (grants 1R01HL 106511-01A1 and R01AG043930), the Velux Stiftung Research Grant Program and the Swiss National Science Foundation (grants 31003A-124713 and CRSII3-136201).
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Glossary
- Mitochondrial DNA
-
(mtDNA). A 16.5 kb circular DNA sequence carried within mitochondria, composed of a light and heavy strand. Both strands contain 37 genes, including 13 that encode protein subunits of the oxidative phosphorylation complexes, whereas the remaining encode ribosomal RNA and tRNA molecules that are essential for the transcription and synthesis of mitochondrially encoded proteins.
- Oxidative phosphorylation
-
Enzymatic phosphorylation of ADP to ATP, which is coupled to electron transfer from a substrate to molecular oxygen in the electron transport chain.
- Heteroplasmy
-
A mixture of different forms of mitochondrial DNA within a single cell.
- Quantitative trait loci
-
(QTLs). Genetic loci contributing quantitatively to a trait or phenotype. A QTL partly explains the genetic contribution to a given phenotype.
- Proteostasis
-
Homeostasis of the protein folding landscape.
- mtDNA haplogroup
-
A group sharing the same single nucleotide polymorphism on mitochondrial DNA (mtDNA). Some haplogroups have been suggested to have a greater likelihood of predisposing individuals to Alzheimer's disease.
- Caloric restriction diet
-
A diet that involves the consumption of 20–50% less calories than normal without causing malnutrition: that is, with maintenance of proper vitamin and mineral intake.
- NAD+
-
The oxidized version of NAD; serves as a co-factor in oxidation–reduction reactions. NAD+ also acts as an obligatory co-substrate for sirtuin-mediated deacylation reactions.
- Inverse agonists
-
Compounds that bind to the same receptor binding site as a prototypical agonist for that given receptor. Through this binding, inverse agonists reverse the basal or constitutive activity of the receptor. Oestrogen-related receptor-α is an example of a constitutively active nuclear receptor for which inverse agonists exist.
- Myokine
-
A signalling molecule that is produced by the muscle and has cytokine-like properties.
- Mitokine
-
A signalling molecule that is produced by mitochondria in a given tissue and affects mitochondrial function in a distinct tissue.
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Andreux, P., Houtkooper, R. & Auwerx, J. Pharmacological approaches to restore mitochondrial function. Nat Rev Drug Discov 12, 465–483 (2013). https://doi.org/10.1038/nrd4023
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DOI: https://doi.org/10.1038/nrd4023
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