MiP2005: Session 10
Mitochondrial Physiology Network 10.9: 114-115 (2005) - download pdf
H Visch1,2, PHGM Willems1, S Grefte1, LWPJ van den Heuvel2, JAM Smeitink2, LG Nijtmans2, Werner JH Koopman1,3
1Depts. Biochemistry; 2Paediatrics; 3Microscopical Imaging Ctr., Nijmegen Ctr. Molecular Life Sciences1,3; 2Mitochondrial Disorders, Radboud Univ., Nijmegen, The Netherlands. - firstname.lastname@example.org
Mutations in nuclear-encoded subunits of NADH:ubiquinone oxidoreductase (complex I) cause complex I deficiency (OMIM 252010), which is associated with a broad spectrum of clinical presentations. Currently, the cellular consequences of these disorders remain elusive and rational treatment strategies are lacking. We recently demonstrated that mitochondrial complexity is increased upon inhibition of complex I  and linearly correlated with residual complex I activity in patient cells . This finding suggests that an increase in mitochondrial complexity might reduce complex I deficiency. Here, we investigated this idea in a collection of 13 patients carrying mutations in nuclear-encoded subunits of complex I (NDUFV1, NDUFS1, NDUFS2, NDUFS4, NDUFS7 or NDUFS8). Cluster analysis highlighted two classes of patients within this cohort displaying a relatively low (class I: 33±3 % of lowest control) or high (class II: 65±3 %) residual complex I activity. Mitochondrial complexity was significantly lower in class I (68±4 % of control) than in class II (115±3 %) and not related to the activity of complex III and IV. Under resting conditions, patient cells displayed a normal cytosolic calcium homeostasis but an increased rate of ROS generation. The latter was fully normalized by treatment with the vitaminic antioxidant Trolox. Both in vehicle and Trolox-treated patient cells complex I activity and assembly were linearly (y=x) correlated. This suggests that complex I, once fully assembled, displays normal catalytic activity. In class I, treatment with Trolox fully restored mitochondrial complexity and enhanced the expression and activity of complex I by 200 %. In class II, Trolox did not affect mitochondrial complexity and increased complex I expression and activity by 50 %. Such restoration was induced by treatment with the mitochondria-targeted antioxidant mitoquinone (MitoQ). We conclude that nuclear-encoded mutations in complex I affect the assembly of the complex but, once assembled, not its catalytic activity. The reduced expression of complex I results in enhanced levels of ROS that contribute to the cellular phenotype by affecting mitochondrial complexity and complex I expression/activity. The effectiveness of Trolox might indicate a potential beneficial role in the treatment of patients.
1. Koopman WJH, Verkaart S, Visch HJ, van der Westhuizen FH, Murphy MP, van den Heuvel LWPJ, Smeitink JAM, Willems PHGM. (2005) Inhibition of complex I of the electron transport chain causes oxygen radical-mediated mitochondrial outgrowth. Am. J. Physiol. Cell Physiol. 288: C1440-C1450.
2. Koopman WJH, Visch, H., Verkaart, S., van den Heuvel, LWPJ, Smeitink, J.A.M., Willems, P.H.G.M. (2005) Mitochondrial network complexity and pathological decrease in complex I activity are tightly correlated in isolated human complex I deficiency. Am. J. Physiol. Cell Physiol. (in press).
3. Boxma B, de Graaf RM, van der Staay GW, van Alen TA, Ricard G, Gabaldon T, van Hoek AH, Moon-van der Staay SY, Koopman WJH, van Hellemond JJ, Tielens AG, Friedrich T, Veenhuis M, Huynen MA, Hackstein JH. (2005) An anaerobic mitochondrion that produces hydrogen. Nature 434: 74-79.