Stem cells and mitochondria //
Science

Mitochondria

Mitochondria are cellular powerplants that produce energy in the form of ATP for the cells needs. In addition to the energy production, mitochondria serve fundamental roles in cellular signaling, generating and regulating reactive oxygen species (ROS), buffering cytosolic calcium levels and regulating apoptosis. Mitochondria are dynamic organelles that undergo active fission and fusion and both mitochondrial mass and activity are regulated constantly.

Mitochondria possess multiple copies of their own DNA and are under dual genetic control by nuclear genome and their own genome.

Mitochondrial disease

Mitochondria play a role in several human disorders, and since both nuclear and mitochondrial DNA encode mitochondrial proteins, mutations in both genomes can lead to mitochondrial disorders. The manifestations of these diseases vary from infantile multisystem disorders to adult-onset myopathies and neurodegeneration, and indeed, mitochondrial disease can occur in any organ-system, with any age of onset. The most commonly affected tissues are those that need most energy, namely the brain and the heart.

Cells contain hundreds of mitochondria, each of which contains hundreds of copies of mtDNA. When a mutation occurs in mtDNA, it creates a mixed population of normal and mutant mtDNA, a state called heteroplasmy, which is typical for pathogenic mtDNA mutations. A threshold for an mtDNA mutation, meaning the amount of mutant mtDNA needed to manifest as respiratory chain deficiency and disease, can vary between tissues and individuals.

The pathological mechanisms underlying mitochondrial disease mechanisms are largely unknown. This is mainly due to the lack of proper experimental model systems. Introduction of exogenous DNA to mitochondria has been unsuccessful, preventing generation of animal models. Better experimental models are needed for mtDNA disorders, because of the common occurrence of mtDNA mutations, their highly tissue-specific phenotypes and unknown disease mechanisms.

Stem cell derived models

Induced pluripotent stem (iPS) cells are somatic cells that have been reprogrammed back to a pluripotent stem cell stage. Similarly to embryonic stem cells, they can differentiate to any cell type found in the adult body. Since they can be derived from patients, they have opened up new ways to use patient cells in research. Using this technology it is possible to study disease mechanisms in living patient neurons or cardiac cells, or any other cell type that would otherwise not be available for research purposes.

Selected publications

  • Ahlqvist KJ, Suomalainen A, Hämäläinen RH. Stem cells, mitochondria and aging. Biochim Biophys Acta. 2015 Nov;1847(11):1380-6.
  • Hämäläinen RH, Ahlqvist KJ, Ellonen P, Lepistö M, Logan A, Otonkoski T, Murphy MP, Suomalainen A. mtDNA Mutagenesis Disrupts Pluripotent Stem Cell Function by Altering Redox Signaling. Cell Rep. 2015 Jun 16;11(10):1614-24.
  • Ahlqvist KJ, Leoncini S, Pecorelli A, Wortmann SB, Ahola S, Forsström S, Guerranti R, De Felice C, Smeitink J, Ciccoli L, Hämäläinen RH, Suomalainen A. MtDNA mutagenesis impairs elimination of mitochondria during erythroid maturation leading to enhanced erythrocyte destruction. Nat Commun. 2015 Mar 9;6:6494.
  • Hämäläinen RH. Induced pluripotent stem cell-derived models for mtDNA diseases. Methods Enzymol. 2014;547:399-415.
  • Hämäläinen RH, Manninen T, Koivumäki H, Kislin M, Otonkoski T, Suomalainen A. Tissue- and cell-type-specific manifestations of heteroplasmic mtDNA 3243A>G mutation in human induced pluripotent stem cell-derived disease model. Proc Natl Acad Sci U S A. 2013 Sep 17;110(38):E3622-30.
  • Ahlqvist KJ, Hämäläinen RH, Yatsuga S, Uutela M, Terzioglu M, Götz A, Forsström S, Salven P, Angers-Loustau A, Kopra OH, Tyynismaa H, Larsson NG, Wartiovaara K, Prolla T, Trifunovic A, Suomalainen A. Somatic progenitor cell vulnerability to mitochondrial DNA mutagenesis underlies progeroid phenotypes in polg mutator mice. Cell Metab. 2012 Jan 4;15(1):100-9.
  • Hussein SM, Batada NN, Vuoristo S, Ching RW, Autio R, Närvä E, Ng S, Sourour M, Hämäläinen R, Olsson C, Lundin K, Mikkola M, Trokovic R, Peitz M, Brustle O, Bazett-Jones DP, Alitalo K, Lahesmaa R, Nagy A, Otonkoski T. Copy number variation and selection during reprogramming to pluripotency. Nature. 2011 Mar 3;471(7336):58-62.
  • Woltjen K, Michael IP, Mohseni P, Desai R, Mileikovsky M, Hämäläinen R, Cowling R, Wang W, Liu P, Gertsenstein M, Kaji K, Sung HK, Nagy A. piggyBac transposition reprograms fibroblasts to induced pluripotent stem cells. Nature. 2009 Apr 9;458(7239):766-70.