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Mitochondrial Physiology

Calcium homeostasis and oxidative stress

Due to their large negative membrane potential, mitochondria can accumulate significant amounts of Ca2+ provided that the ambient Ca2+ concentration is sufficiently high. The latter is achieved by close juxtaposition of these organelles against the endoplasmic reticulum (ER), which forms the major source of Ca2+ ions during cellular stimulation. The increase in mitochondrial Ca2+ concentration causes a boost in mitochondrial ATP production, thus allowing the rapid balancing of local energy demand.
 
Using a combination of luminometry (cell groups) and digital imaging microscopy (single cells), we have found that Ca2+-stimulated mitochondrial ATP production is decreased in skin fibroblasts of patients with inherited complex I deficiency and that this decrease is mainly due to a pathological reduction in ER Ca2+ content. Thus far, we have shown that drugs that normalize the agonist-induced increase in mitochondrial Ca2+ concentration also normalize the agonist-induced increase in mitochondrial ATP production.

Our findings are of eminent importance because they provide possible drug targets for the amelioration of the condition of patients suffering from isolated complex I deficiency. New projects will be started to evaluate possible beneficial effects of drugs that interfere with Ca2+-stimulated mitochondrial ATP production.

Recent publications

  1. Broad defects in the energy metabolism of leukocytes underlie immunoparalysis in sepsis. Cheng SC, Scicluna BP, Arts RJ, Gresnigt MS, Lachmandas E, Giamarellos-Bourboulis EJ, Kox M, Manjeri GR, Wagenaars JA, Cremer OL, Leentjens J, van der Meer AJ, van de Veerdonk FL, Bonten MJ, Schultz MJ, Willems PH, Pickkers P, Joosten LA, van der Poll T, Netea MG. Nat Immunol. 2016 Apr;17(4):406-13. doi: 10.1038/ni.3398. Epub 2016 Mar 7. PubMed PMID: 26950237.

  2. Complex I and complex III inhibition specifically increase cytosolic hydrogen peroxide levels without inducing oxidative stress in HEK293 cells. Forkink M, Basit F, Teixeira J,Swarts HG, Koopman WJ, Willems PH.  Redox Biol. 2015 Oct 23;6:607-616.

  3. Increased mitochondrial ATP production capacity in brain of healthy mice and a mouse model of isolated complex I deficiency after isoflurane anesthesia. Manjeri GR, Rodenburg RJ, Blanchet L, Roelofs S, Nijtmans LG, Smeitink JA, Driessen JJ, Koopman WJ, Willems PH. J Inherit Metab Dis. 2015 Aug 27.

  4. Rotenone inhibits primary murine myotube formation via Raf-1 and ROCK2. Grefte S, Wagenaars JAL, Jansen R, Willems PHGM, Koopman WJH. BBA Molecular Cell Research. 2015 Jul;1853(7):1606-14. Epub 2015 Mar 28.

  5. Redox Homeostasis and Mitochondrial Dynamics. Willems PH, Rossignol R, Dieteren CE, Murphy MP, Koopman WJ. Cell Metab. 2015 Aug 4;22(2):207-18. doi: 10.1016/j.cmet.2015.06.006.

  6. Interactions between mitochondrial reactive oxygen species and cellular glucose metabolism. Liemburg-Apers DC, Willems PH, Koopman WJ, Grefte S. Arch Toxicol .2015 Jun 6. [Epub ahead of print]

  7. Mitochondrial dysfunction in primary human fibroblasts triggers an adaptive cell survival program that requires AMPK-α. Distelmaier F, Valsecchi F, Liemburg-Apers DC, Lebiedzinska M, Rodenburg RJ, Heil S, Keijer J, Fransen J, Imamura H, Danhauser K, Seibt A, Viollet B, Gellerich FN, Smeitink JA, Wieckowski MR, Willems PH, Koopman WJ. Biochim Biophys Acta. 2015 Mar;1852(3):529-40.

  8. Skeletal muscle mitochondria of NDUFS4(-/-) mice display normal maximal pyruvate oxidation and ATP production. Alam MT, Manjeri GR, Rodenburg RJ, Smeitink JA, Notebaart RA, Huynen M, Willems PH, Koopman WJ. Biochim Biophys Acta. 2015 Feb 14. pii: S0005-2728(15)00031-6.

  9. Toward high-content screening of mitochondrial morphology and membrane potential in living cells. Iannetti EF, Willems P, Pellegrini M, Beyrath J, Smeitink J, Blanchet L, Koopman WJ. Int J Biochem Cell Biol. 2015 Feb 8. pii:S1357-2725(15)00030-8.

  10. Live-cell assessment of mitochondrial reactive oxygen species using dihydroethidine. Forkink M, Willems PH, Koopman WJ, Grefte S. Methods Mol Biol. 2015;1264:161-9

  11. Quantifying small molecule phenotypic effects using mitochondrial morpho-functional fingerprinting and machine learning. Blanchet L, Smeitink JA, van Emst-de Vries SE, Vogels C, Pellegrini M, Jonckheere AI, Rodenburg RJ, Buydens LM, Beyrath J, Willems PH, Koopman WJ. Sci Rep. 2015 Jan 26;5:8035.

  12. Mitochondrial hyperpolarization during chronic complex I inhibition is sustained by low activity of complex II, III, IV and V. Forkink M, Manjeri GR, Liemburg-Apers DC, Nibbeling E, Blanchard M, Wojtala A, Smeitink JA, Wieckowski MR, Willems PH, Koopman WJ. Biochim Biophys Acta. 2014 Aug;1837(8):1247-56.

  13. Mitochondrial diseases: Drosophila melanogaster as a model to evaluate potential therapeutics. Foriel S, Willems P, Smeitink J, Schenck A, Beyrath J. Int J Biochem Cell Biol. 2015 Feb 7.

  14. Mitochondrial dysfunction in primary human fibroblasts triggers an adaptive cell survival program that requires AMPK-α. Distelmaier F, Valsecchi F, Liemburg-Apers DC, Lebiedzinska M, Rodenburg RJ, Heil S, Keijer J, Fransen J, Imamura H, Danhauser K, Seibt A, Viollet B, Gellerich FN, Smeitink JA, Wieckowski MR, Willems PH, Koopman WJ. Biochim Biophys Acta. 2015 Mar;1852(3):529-40.