Advances in mt-tRNA Mutation-Caused Mitochondrial Disease Modeling: Patients’ Brain in a Dish

Abstract

Mitochondrial diseases are a heterogeneous group of rare genetic disorders that can be caused by mutations in nuclear (nDNA) or mitochondrial DNA (mtDNA). Mutations in mtDNA are associated with several maternally inherited genetic diseases, with mitochondrial dysfunction as a main pathological feature. These diseases, although frequently multisystemic, mainly affect organs that require large amounts of energy such as the brain and the skeletal muscle. In contrast to the difficulty of obtaining neuronal and muscle cell models, the development of induced pluripotent stem cells (iPSCs) has shed light on the study of mitochondrial diseases. However, it is still a challenge to obtain an appropriate cellular model in order to find new therapeutic options for people suffering from these diseases. In this review, we deepen the knowledge in the current models for the most studied mt-tRNA mutation-caused mitochondrial diseases, MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes) and MERRF (myoclonic epilepsy with ragged red fibers) syndromes, and their therapeutic management. In particular, we will discuss the development of a novel model for mitochondrial disease research that consists of induced neurons (iNs) generated by direct reprogramming of fibroblasts derived from patients suffering from MERRF syndrome. We hypothesize that iNs will be helpful for mitochondrial disease modeling, since they could mimic patient’s neuron pathophysiology and give us the opportunity to correct the alterations in one of the most affected cellular types in these disorders.

Leigh Syndrome: A Tale of Two Genomes

“…One of the challenges with iPSC models is the ability to maintain mutation load in daughter cells after reprogramming and differentiation ( Povea-Cabello et al, 2020 ). To address this problem, direct reprogramming protocols have been developed to ensure that the age and epigenetic markers of donors are maintained ( Horvath, 2013 ; Mertens et al, 2015 ; Huh et al, 2016 ).…”

“…The biggest challenge of all relates to maintaining these cell lines in long-term culture. The long-term culture of iPSC and reprogramming is difficult and extremely expensive, making it difficult to adopt in labs with limited resources ( Povea-Cabello et al, 2020 ). However, direct reprogramming, like those done to derive iNs can help reduce the cost of reprogramming hiPSC.…”

“…The pharmacological therapies focus on different aspects of mitochondrial function, ranging from upregulation of mitochondrial biogenesis or autophagy to preventing oxidative damage ( Lightowlers et al, 2015 ; Gerards et al, 2016 ; Povea-Cabello et al, 2020 ). The most common targets for pharmacological agents focus on AMP-activated protein kinase (AMPK), Sirtuins (Sirt1), and mammalian target of rapamycin complex 1 (mTORC1) pathways ( Garone and Viscomi, 2018 ; Viscomi and Zeviani, 2020 ).…”

Late onset of type 2 diabetes is associated with mitochondrial tRNATrp A5514G and tRNASer(AGY) C12237T mutations

“…Human mitochondrial genome is a relative small molecule (16,569‐bp long) which encodes 13 polypeptides, 2 rRNAs (12S rRNA and 16S rRNA), and 22 tRNAs 7 . Despite the fact that the entire mt‐tRNA genes account only for approximately 10% of total mitochondrial genome, more than 2/3 mitochondrial disease‐related pathogenic mutations are localized at tRNA genes 8,9 . Among these mutations, the A to G substitution at position 3243 appears to be the most common T2DM‐associated pathogenic mutation 10–12 .…”

“… 7 Despite the fact that the entire mt‐tRNA genes account only for approximately 10% of total mitochondrial genome, more than 2/3 mitochondrial disease‐related pathogenic mutations are localized at tRNA genes. 8 , 9 Among these mutations, the A to G substitution at position 3243 appears to be the most common T2DM‐associated pathogenic mutation. 10 , 11 , 12 Furthermore, several case‐control studies indicate that tRNA Ile T4291C, 13 tRNA Glu A14692G, and T14709C mutations 14 , 15 are involved in the pathogenesis of T2DM.…”