Impairment of PINK1/parkin-mediated mitophagy is currently proposed to be the molecular basis of mitochondrial abnormality in Parkinson's disease (PD). We here demonstrate that PINK1 directly phosphorylates Drp1 on S616. Drp1 S616 phosphorylation is significantly reduced in cells and mouse tissues deficient for PINK1, but unaffected by parkin inactivation. PINK1-mediated mitochondrial fission is Drp1 S616 phosphorylation dependent. Overexpression of either wild-type Drp1 or of the phosphomimetic mutant Drp1 S616D , but not a dephosphorylation-mimic mutant Drp1 S616A , rescues PINK1 deficiency-associated phenotypes in Drosophila. Moreover, Drp1 restores PINK1-dependent mitochondrial fission in ATG5-null cells and ATG7-null Drosophila. Reduced Drp1 S616 phosphorylation is detected in fibroblasts derived from 4 PD patients harboring PINK1 mutations and in 4 out of 7 sporadic PD cases. Taken together, we have identified Drp1 as a substrate of PINK1 and a novel mechanism how PINK1 regulates mitochondrial fission independent of parkin and autophagy. Our results further link impaired PINK1-mediated Drp1 S616 phosphorylation with the pathogenesis of both familial and sporadic PD.

3.

Purpose To investigate the clinical efficacy and feasibility of one-stage surgical treatment for upper thoracic spinal tuberculosis by internal fixation, debridement, and combined interbody and posterior fusion via a posterioronly approach. Methods Fourteen patients (eight males, six females) with upper thoracic tuberculosis whose lesions were confined to two adjacent segments were admitted to our hospital. Their ages ranged from 23 to 72 years (average, 50 years). The American Spinal Injury Association (ASIA) impairment scale was used to assess neurological function. ASIA classification showed that preoperatively, one patient was grade A, two patients were grade B, eight patients were grade C, and three patients were grade D. All patients were treated with one-stage surgical treatment by internal fixation, debridement, and combined interbody and posterior fusion via a posterior-only approach. Patients were evaluated preoperatively and postoperatively by measurement of thoracic kyphotic angles using Cobb angle evaluation, determination of erythrocyte sedimentation rate (ESR), evaluation of ASIA impairment scale, and radiological examination. Results Operation time ranged from 70 to 135 min, (average, 110 min). Intraoperative blood loss ranged from 200 to 950 mL (average, 450 mL). All patients were followed up for 22 to 48 months postoperatively (average, 31.5 months). No sinus tract formation, cerebrospinal meningitis, or recurrence of tuberculosis occurred. All patients had significant postoperative improvement in ASIA classification scores. The thoracic kyphotic angles were significantly decreased to 12°-26°postoperatively, and at final follow-up were 13°-28°. The ESR recovered to normal within 6 months postoperatively in all patients. Bone fusion was achieved within 3-8 months (average, 5.5 months). Conclusions One-stage surgical treatment for upper thoracic spinal tuberculosis by internal fixation, debridement, and combined interbody and posterior fusion via a posterior-only approach can be an effective and feasible treatment method.