BackgroundParkinson's disease (PD) is an adult-onset movement disorder of largely unknown etiology. We have previously shown that loss-of-function mutations of the mitochondrial protein kinase PINK1 (PTEN induced putative kinase 1) cause the recessive PARK6 variant of PD.Methodology/Principal FindingsNow we generated a PINK1 deficient mouse and observed several novel phenotypes: A progressive reduction of weight and of locomotor activity selectively for spontaneous movements occurred at old age. As in PD, abnormal dopamine levels in the aged nigrostriatal projection accompanied the reduced movements. Possibly in line with the PARK6 syndrome but in contrast to sporadic PD, a reduced lifespan, dysfunction of brainstem and sympathetic nerves, visible aggregates of α-synuclein within Lewy bodies or nigrostriatal neurodegeneration were not present in aged PINK1-deficient mice. However, we demonstrate PINK1 mutant mice to exhibit a progressive reduction in mitochondrial preprotein import correlating with defects of core mitochondrial functions like ATP-generation and respiration. In contrast to the strong effect of PINK1 on mitochondrial dynamics in Drosophila melanogaster and in spite of reduced expression of fission factor Mtp18, we show reduced fission and increased aggregation of mitochondria only under stress in PINK1-deficient mouse neurons.ConclusionThus, aging Pink1−/− mice show increasing mitochondrial dysfunction resulting in impaired neural activity similar to PD, in absence of overt neuronal death.

The molecular mechanisms determining mitochondrial architecture are largely unclear. The C-terminal domain of Fcj1 and the TOB complex are shown to interact. Both are important for determining cristae morphology. The results explain how crista junctions are positioned at the outer membrane, assigning novel functions to both Fcj1 and the TOB complex.

Mitochondrial membrane architecture is important for organelle function. Alterations thereof are linked to a number of human disorders including diabetes and cardiomyopathy. The MICOS complex was recently reported to be a central player determining cristae structure and formation of crista junctions. Here we investigated the functional role of MIC26, a lipoprotein formerly termed APOO. Its levels are increased in diabetic heart tissue and in blood plasma of patients suffering from acute coronary syndrome. We demonstrate that human MIC26 exists in three distinct forms: (1) a glycosylated and secreted 55kDa protein, (2) an ER/Golgi-resident form thereof, and (3) a non-glycosylated 22kDa mitochondrial protein. The latter isoform spans the mitochondrial inner membrane and physically interacts with several MICOS complex subunits such as MIC60, MIC27, and MIC10. We further demonstrate that MIC26 and MIC27, a homologous protein formerly termed APOOL, regulate their levels in an antagonistic manner. Both proteins are positively correlated with the levels of MIC10 as well as tafazzin, an enzyme required for cardiolipin remodeling. Overexpression of MIC26 induced fragmentation of mitochondria, promoted ROS formation and resulted in impaired mitochondrial respiration. Downregulation of MIC26 induced a decrease in mitochondrial oxygen consumption, whereas mitochondrial network morphology and ROS levels remained unaffected. MIC26 depletion led to alterations in mitochondrial ultrastructure and caused a significant reduction in the number of crista junctions. In summary, we show that the human apolipoprotein MIC26 is a bona fide subunit of the MICOS complex and that MIC26 is linked to cardiolipin metabolism and promotes crista junction formation.

Edited by Miguel De la RosaRemodeling of crista junctions (CJs) is observed in numerous human disorders and during apoptosis. The functional interplay of OPA1 and MIC60, two key players in this context, is unclear. We show that OPA1 modulates cristae morphology but is dispensable for CJ formation. MIC60 is strongly enriched at CJs, whereas OPA1 is distributed evenly across the inner membrane. MIC60 levels are increased in OPA1À/À cells which show increased cellular resistance to apoptosis induction. Endogenous OPA1 and MIC60 show a physical interaction. Overall, we suggest that the regulation of CJ remodeling during apoptosis is mediated via an interplay between OPA1 and MIC60.

Two experiments were conducted to determine the effect of supplementation of xylanase to a wheat-based diet on the apparent ileal digestibility (AID) of AA and the performance of growing pigs fed diets limiting in AA. In Exp. 1, eight pigs (average initial BW = 20.5+/-1.2 kg) fitted with a simple T-cannula at the distal ileum, were fed four diets according to a repeated 4 x 4 Latin square design. Diet 1 was a basal diet that contained 97.6% wheat. Diets 2, 3, and 4 were the basal diet supplemented with xylanase at rates of 5,500, 11,000, and 16,500 units of xylanase activity (XU), respectively (as-fed basis). There were linear and quadratic effects (0.062 < P < 0.001) of xylanase supplementation on the AID of CP and most of the AA. The largest increases in AID of CP and AA were obtained when xylanase was supplemented at a rate of 11,000 XU; no further increases were observed with xylanase supplementation at a rate of 16,500 XU. In Exp. 2, 30 pigs (average initial BW 21.4+/-1.8 kg) were randomly allotted to six dietary treatments. Diets 1 to 4 were similar to those used in Exp. 1. Diet 5 was the same as Diet 1, but supplemented with 0.53% lysine, 0.12% threonine, and 0.05% methionine. Diet 6 (positive control diet) was a wheat-soybean meal diet that contained 18.2% CP (as-fed basis). The total contents of lysine, threonine, and methionine were similar for Diets 5 and 6. There was a linear effect of xylanase supplementation on ADG (P = 0.093) and feed:gain ratio (P = 0.089), and a quadratic effect on ADG (P = 0.067) and feed:gain ratio (P = 0.074). But, the greatest response was obtained with the supplementation of 11,000 XU. The supplementation of lysine, threonine, and methionine to Diet 1 increased (P = 0.001) ADG and ADFI and improved (P = 0.01) feed:gain ratio. There was no difference (P = 0.508) in the performance of pigs fed the AA-supplemented or control diet. In conclusion, the supplementation of xylanase to a diet in which wheat provided the sole source of protein and energy improved the AID of AA, ADG, and feed:gain ratio; however, this improvement was very small compared with that obtained with the supplementation of synthetic amino acids.