Stem cells to the rescue of human diseases caused by mitochondrial DNA mutations


Mitochondrial DNA and mitochondrial diseases

Mitochondria is an organelle which is found in several thousand copies within a cell and it has its own genome which is unique in many ways from the nuclear genome. Mitochondrial genome is circular, smaller in size with a mere 16,569 base pairs which contains 37 genes. These genes encode for 13 proteins all of which instruct cells to produce protein subunits of the enzyme complexes of the oxidative phosphorylation system that enables the mitochondria to convert glucose, amino acids and fatty acids into adenosine triphosphate (ATP) and makes it the energy powerhouse of the cell.

Despite the small size of the genome, due to an imbalance in the dGTP levels and a low fidelity DNA polymerase (encoded by the gene POLG) the mitochondrial DNA is highly susceptible to mutations.

Interestingly, the mode of inheritance of the mitochondrial DNA is strictly maternal, unlike the nuclear genome which is equally inherited from both the parent cells. Thus mitochondria-linked disease mutation are always maternally inherited. The diseases focused for the purpose of this study are the MELAS syndrome (Mitochondrial Encephalomyopathy, Lactic Acidosis and Stroke-like episodes) and the Leigh syndrome (infantile or juvenile subacute necrotizing encephalomyelopathy) both of which are rare inherited neurometabolic disorders affecting the brain and nervous system (encephalo-) and muscles (myopathy).

They are mainly caused by mutations in the mitochondrial DNA, which affect the proteins involved in oxidative phosphorylation and thus in high energy consuming organs like the brain and muscle systems these mutations are highly debilitating, progressive and even fatal. There are no known treatments for these diseases and hence research directed towards the understanding of these diseases and the lookout for possible treatment modalities becomes very crucial and important.

Somatic cell nuclear transfer to generate stem cells

Watch a video on Somatic Cell Nuclear Transfer here.

Hong Ma and Shoukhrat Mitalipov’s group at Oregon Health & Science University and Oregon National Primate Research Center has devised a novel strategy to employ gene and stem cell therapy towards regenerative medicine for patients with mitochondrial disease. They have utilized their previously published technique of reprogramming somatic cells into pluripotent embryonic stem cells (ESCs) by somatic cell nuclear transfer (SCNT) for generating patient-matched nuclear transfer (NT)-ESCs.

In this dolly-like approach, the scientists carried out nuclear transfer from skin cells of patients with mitochondrial diseases into healthy oocyte cytoplasm thereby replacing the mitochondrial content in the resulting pluripotent stem cells (PSCs) making them healthy. Genetically-rescued PSCs displayed normal nuclear-to-mitochondrial interactions, metabolic function compared to impaired oxygen consumption and ATP production observed in mutant cells.

This nuclear transfer technique is more precise than conventional gene therapy techniques. Such mitochondrial replacement can pave the way for reinserting genetically corrected cells in to the patient to replace diseased tissue and meet the energy demands of the affected organs.

“This is an important advancement in the quest to develop treatments for those affected by mitochondrial disease”, said Philip Yeske, Science and Alliance Officer for the United Mitochondrial Disease Foundation.” Mitochondrial replacement holds great therapeutic potential, and the patient community looks forward to further progress on the path toward clinical applications.” This study is an excellent application of iPSC technology and SCNT, which when synergized hold great potential for patient specific cell replacement therapies.


  1. An ovum is used for this technique (from the video), which would be for females.
    what about males ?
    Which cells would be used ?
    I apologize if the question is stupid, but i am just a college student.
    It just popped into my head.

    • To understand the work described here, it is good to understand the concept of somatic cell nuclear transfer wherein a somatic cell’s nucleus or DNA content (therapeutic or healthy) is transferred to an ovum (could be healthy or disease) to create embryonic stem cells (or in certain cases an organism) which become therapeutic. One cannot replace the oocyte with a spermatocyte simply because the process of developmental biology absolutely requires oocytes for the generation of embryonic stem cells. An alternative generation of induced pluripotent stem cells gene corrected to remove the mutations is a possible futuristic resource which can use any patient-derived cell type with the current advances in technology.

      Also, mitochondrial DNA is strictly inherited maternally and paternal (sperm-derived) mitochondrial DNA is usually eliminated during development. In this study the diseases, MELAS and Leigh Syndrome, are both maternally inherited diseases so they delivered a patient’s fibroblast-derived nuclear DNA to an oocyte containing healthy mitochondrial DNA to produce healthy embryonic stem cells not carrying the debilitating mitochondrial mutations. This pool of healthy NT-ESCs could be further differentiated into specific lineages and reinserted into the patient to repopulate the damaged tissue and address the metabolic demand of the patient.