Koopman 2012 Abstract Bioblast

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Koopman WJ (2012) Cellular consequences of mitochondrial dysfunction. Mitochondr Physiol Network 17.12.

Link: MiPNet17.12 Bioblast 2012 - Open Access

Koopman WJ (2012)

Event: Bioblast 2012

Werner Koopman

To function normally, human cells require energy in the form of ATP that is generated by a variety of metabolic pathways. In most cell types ATP is primarily produced by the mitochondrial oxidative phosphorylation (OXPHOS) system. The latter consists of 5 multi-subunit complexes (complex I to complex V) that contain 92 different structural proteins encoded by the nuclear (nDNA) and mitochondrial DNA (mtDNA). Biogenesis of a functional OXPHOS system further requires the assistance of nDNA-encoded OXPHOS assembly factors (chaperones), of which 35 are currently identified. Importantly, mitochondria do not only generate ATP but also play key roles in other important cellular processes, such as adaptive thermogenesis, ion homeostasis, innate immune responses, production of reactive oxygen species (ROS), and programmed cell death (apoptosis). Mitochondrial dysfunction is not only associated with relatively rare monogenic mitochondrial disorders but is also observed during more common pathologic conditions, such as Alzheimer’s disease, Parkinson’s disease, cancer, cardiac disease, diabetes, epilepsy, Huntington’s disease, and obesity. In addition, mitochondrial function is inhibited by environmental toxins and frequently used drugs. Also during normal human aging, a progressive decline in the expression of mitochondrial genes is observed. Mutations in OXPHOS structural genes are associated with neurodegenerative diseases including Leigh syndrome, which is probably the most classical OXPHOS disease during early childhood. During the last decade analysis of cells from patients with monogenic mitochondrial diseases has considerably advanced our general understanding of the cellular (patho)physiology of mitochondrial (dys)function. Here it will be summarized how these insights were obtained and how they can contribute to the rational design of intervention strategies for mitochondrial dysfunction. To this end, our on-going research on human mitochondrial complex I deficiency will be presented as an example of mitochondrial medicine.

  1. Koopman WJH, Distelmaier F, Smeitink JAM, Willems PHGM (2012) OXPHOS mutations and neurodegeneration. EMBO J (in press).
  2. Willems PHGM, Wanschers B, Esseling J, Szklarzyk R, Kudla U, Duarte I, Nooteboom M, Forkink M, Swarts H, Gloerich J, Nijtmans LJ, Koopman WJH, Huynen M (2012) BOLA1 is an aerobic protein that prevents mitochondrial morphology changes induced by glutathione depletion. Antioxidants and redox signaling 18: 1-10.
  3. Distelmaier F, Valsecchi F, Forkink M, van Emst-de Vries S, Swarts H, Rodenburg R, Verwiel E, Smeitink J, Willems PHGM, Koopman WJH (2012) Trolox-sensitive ROS regulate mitochondrial morphology, oxidative phosphorylation and cytosolic calcium handling in healthy cells. Antioxidants and redox signaling 17: 1657-1669.

Mitochondrial disorders, Complex I, ROS, Mitochondrial dynamics, Calcium, Therapies MiPNetLab: NL Nijmegen Koopman WJ


Labels: Mammal;model: Human  Enzyme: Complex I Stress: Mitochondrial disease HRR: Oxygraph-2k 



Affiliations and author contributions

Department of Biochemistry (286) NCMLS, Radboud University Medical Centre, Nijmegen, The Netherlands. E-mail: W.koopman@ncmls.ru.nl

Figure 1

Primary mitochondrial disorders

Mitochondrial disorders can be of the primary or secondary category. At the cellular level, the mitochondrial protein mutation has primary and secondary consequences ultimately leading to pathology. Several cellular feedback mechanisms exist that (partially) counterbalance (green line) the effects of the mitochondrial dysfunction. Possible intervention strategies are indicated by dotted lines (see Koopman et al., NEJM, 2012 for details).


Supplementary references

  1. Koopman WJH, Willems PHGM, Smeitink JAM (2012) Monogenic mitochondrial disorders. New Eng J Med 366: 1132-1141.
  2. Dieteren CEJ, Gielen SCAM, Nijtmans LGJ, Smeitink JAM, Swarts HG, Brock R, Willems PHGM, Koopman WJH (2011) Solute diffusion is hindered in the mitochondrial matrix. Proc Natl Acad Sci U S A 108: 8657-8662.
  3. Koopman WJH, Nijtmans LG, Dieteren CEJ, Roestenberg P, Valsecchi F, Smeitink JAM, Willems PHGM (2010) Mammalian mitochondrial complex I: Biogenesis, regulation and reactive oxygen species generation. Antioxidants and redox signaling 12: 1431-1470.
  4. Distelmaier F, Koopman WJH, van den Heuvel LW, Rodenburg RJ, Mayatepek E, Willems PHGM, Smeitink JAM (2009) Mitochondrial complex I deficiency: From organelle dysfunction to clinical disease. Brain 132: 833-842.


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