Abstract
Mitochondrial medicine is an exciting and rapidly evolving field. While the mitochondrial genome is small and differs from the nuclear genome in that it is circular and free of histones, it has been implicated in neurodegenerative diseases, type 2 diabetes, aging and cardiovascular disorders. Currently, there is a lack of efficient treatments for mitochondrial diseases. This has promoted the need for developing an appropriate platform to investigate and target the mitochondrial genome. However, developing these therapeutics requires a model system that enables rapid and effective studying of potential candidate therapeutics. In the past decade, induced pluripotent stem cells (iPSCs) have become a promising technology for applications in basic science and clinical trials, and have the potential to be transformative for mitochondrial drug development. Engineered iPSC-derived cardiomyocytes (iPSC-CM) offer a unique tool to model mitochondrial disorders. Additionally, these cellular models enable the discovery and testing of novel therapeutics and their impact on pathogenic mtDNA variants and dysfunctional mitochondria. Herein, we review recent advances in iPSC-CM models focused on mitochondrial dysfunction often causing cardiovascular diseases. The importance of mitochondrial disease systems biology coupled with genetically encoded NAD+/NADH sensors is addressed toward developing an in vitro translational approach to establish effective therapies.
Highlights
Mitochondria are fundamental structures in eukaryotes since they play a dynamic role in cellular metabolism and are critical for Adenosine triphosphate (ATP) production
To overcome the challenges of NAD+/Nicotinamide adenine dinucleotide (NADH) dynamics analysis with subcellular resolution in vivo, we propose a new technology using a genetically encoded fluorescent sensor based on fluorescent proteins (FPs) with the ability to analyze NAD+/NADH dynamics with subcellular resolution
We propose that human iPSCderived cardiomyocytes provide a unique translational model system to advance understanding of mitochondrial pathogenic variants. These cellular models have the potential for investigating mitochondrial dysfunction caused by mitochondrial DNA (mtDNA) variants, and as a drug screening platform for both mitochondrial and cardiovascular disorders
Summary
Mitochondria are fundamental structures in eukaryotes since they play a dynamic role in cellular metabolism and are critical for ATP production. IPSC-CM technology greatly facilitates the study of genetic cardiovascular diseases, development of cardiovascular system, toxicological screening, drug discovery, and personalized cell-based therapy [50] While these cardiomyopathy hiPSC-CM models focused mostly on mutations in sarcomeric genes that regulate cardiomyocyte contraction and calcium handling, a few have showed energy depletion phenotypes due to mitochondrial dysfunction [74, 75]. Most studies relating mutations in mtDNA to cardiovascular disorders rely on large-scale mitochondrial genetics to associate specific variants with patient cohorts exhibiting different cardiac phenotypes [31] While this approach is statistically robust, it lacks functional characterization of pathological phenotypes exhibited by cardiomyocytes in vitro, required to better understand disease progression and treatment. Due to the limitations of conventional methods explored above, genetically encoded fluorescent sensors may present
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