Mitochondrial Medicine: Genetic Underpinnings and Disease Modeling Using Induced Pluripotent Stem Cell Technology

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.

Study of lead-induced neurotoxicity in cholinergic cells differentiated from bone marrow-derived mesenchymal stem cells

“…Creating a human cell model that enables unlimited access is therefore highly valuable for toxicology studies. The most recent model proposed pertains to stem cells and is capable of the dynamic assessment of environmental and chemical stressor substances (Kargaran et al, 2021). The potentially significant benefits of stem cells in toxicology are these cells’ unique features, including their unlimited proliferation capacity, plasticity, production of other cell types, and potential to supply a valuable and accessible human cell source (Davila et al, 2004).…”

Modelling Mitochondrial Disease in Human Pluripotent Stem Cells: What Have We Learned?

“…Mitochondrial disease hPSC models provide a system to study disease gene- or mutation-related pathomechanisms in tissues relevant to the clinical phenotype. Ultimately, the long-term goal of these models would be to identify a phenotype in a clinically relevant cell type that could be used to validate efficacy of targeted treatments, or for use in high-throughput treatment trials [ 94 , 95 , 96 ] ( Figure 2 ).…”

Human induced pluripotent stem cells for studying mitochondrial diseases in the heart

“…understanding of basic mitochondrial phenotype-genotype relationships [7,8]. While the number of promising clinical trials for mitochondrial-targeted therapies has substantially improved in recent years, they still lag behind the speed of diagnosis [9].…”

“…Currently, there are no viable mitochondrial therapies. Drug development of mitochondrial‐targeted therapies is greatly hindered by broad clinical manifestations, genetic heterogeneity and incomplete understanding of basic mitochondrial phenotype–genotype relationships [7,8]. While the number of promising clinical trials for mitochondrial‐targeted therapies has substantially improved in recent years, they still lag behind the speed of diagnosis [9].…”