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Small-molecule Compound Promotes Function of Cells Carrying Mitochondrial Mutations

Review of "Chemical reversal of abnormalities in cells carrying mitochondrial DNA mutations" from Nature Chemical Biology by Stuart P. Atkinson

Mutations in mitochondrial DNA cause disorders associated with oxidative energy metabolism defects [1]. Treatment options include compounds that enhance mitochondrial function or reduce reactive oxygen species levels or lactate in body tissues [2]. As an example, dichloroacetate treatment in MELAS syndrome patients (mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes [3]) suppresses lactate production and activates mitochondrial respiration; however, clinical trials of dichloroacetate have reported significant toxicity [4], and the search for small molecules that enhance respiratory activity via distinct modes of action continues.

Now, a new study from the laboratories of Yu-ichi Goto (National Center of Neurology and Psychiatry, Tokyo) and Minoru Yoshida (RIKEN Center for Sustainable Resource Science, Saitama/The University of Tokyo, Japan), Kobayashi et al. report on a small-molecule compound (tryptolinamide or TLAM, a tryptoline derivative) that activates mitochondrial respiration in cybrids generated from patient-derived mitochondria and fibroblasts from patient-derived induced pluripotent stem cells (iPSCs) and rescue defects to the neuronal differentiation of iPSCs carrying a high ratio of mutant mitochondrial DNA [5].

In brief, the authors first discovered that TLAM treatment effectively activated oxidative phosphorylation in cybrids generated from patient-derived mitochondria and fibroblasts generated from MELAS patient-derived iPSCs. At the mechanistic level, TLAM inhibited phosphofructokinase-1 (PFK1), which catalyzes the irreversible phosphorylation of fructose 6-phosphate to form fructose 1,6-bisphosphate, which usually acts to commit a glucose molecule to the glycolytic pathway [6]. TLAM-mediate inhibition then promotes the activation of 5' AMP-activated protein kinase-mediated fatty-acid oxidation and induces oxidative phosphorylation. TLAM treatment also redirected carbon flow from glycolysis toward the pentose phosphate pathway (a metabolic pathway parallel to glycolysis) and increased NADPH levels, which possesses potent anti-oxidant activity.

Finally, and perhaps most excitingly, the authors established that the treatment of patient-derived iPSCs carrying a high ratio of mutant mitochondrial DNA with TLAM rescued a neuronal differentiation defect by increasing cellular respiratory activity above the threshold that allows normal embryonic differentiation [7], thereby providing evidence for the relevance of TLAM therapy as a treatment for mitochondrial diseases.

For more on how iPSCs and small molecules combine to pave the way towards mitochondrial disease treatments, stay tuned to the Stem Cells Portal!



  1. Schon EA, DiMauro S, and Hirano M, Human mitochondrial DNA: roles of inherited and somatic mutations. Nature Reviews Genetics 2012;13:878-890.
  2. Avula S, Parikh S, Demarest S, et al., Treatment of Mitochondrial Disorders. Current Treatment Options in Neurology 2014;16:292.
  3. Goto Y-i, Nonaka I, and Horai S, A mutation in the tRNALeu(UUR) gene associated with the MELAS subgroup of mitochondrial encephalomyopathies. Nature 1990;348:651-653.
  4. Kaufmann P, Engelstad K, Wei Y, et al., Dichloroacetate causes toxic neuropathy in MELAS. Neurology 2006;66:324.
  5. Kobayashi H, Hatakeyama H, Nishimura H, et al., Chemical reversal of abnormalities in cells carrying mitochondrial DNA mutations. Nature Chemical Biology 2020.
  6. Mor I, Cheung EC, and Vousden KH, Control of Glycolysis through Regulation of PFK1: Old Friends and Recent Additions. Cold Spring Harbor Symposia on Quantitative Biology 2011;76:211-216.
  7. Yokota M, Hatakeyama H, Ono Y, et al., Mitochondrial respiratory dysfunction disturbs neuronal and cardiac lineage commitment of human iPSCs. Cell Death & Disease 2018;8:e2551-e2551.