Mutational burden of XPNPEP3 leads to defects in mitochondrial complex I and cilia in NPHPL1

Lingxiao Tong; Jia Rao; Chenxi Yang; Jie Xu; Yijun Lu; Yuchen Zhang; Xiaohui Cang; Shanshan Xie; Jianhua Mao; Pingping Jiang

doi:10.1016/j.isci.2023.107446

Mutational burden of XPNPEP3 leads to defects in mitochondrial complex I and cilia in NPHPL1

iScience. 2023 Jul 23;26(8):107446. doi: 10.1016/j.isci.2023.107446. eCollection 2023 Aug 18.

Authors

Lingxiao Tong¹, Jia Rao², Chenxi Yang^{1

3}, Jie Xu¹, Yijun Lu³, Yuchen Zhang³, Xiaohui Cang^{1

3}, Shanshan Xie¹, Jianhua Mao^{1

4}, Pingping Jiang^{1

3}

Affiliations

¹ Department of Nephrology, The Children's Hospital, Zhejiang University School of Medicine and National Clinical Research Center for Child Health, Hangzhou, China.
² Department of Nephrology, Children's Hospital of Fudan University, National Pediatric Medical Center of China, Shanghai, China.
³ Department of Human Genetics, Zhejiang University School of Medicine, Hangzhou, China.
⁴ Zhejiang Key Laboratory for Neonatal Diseases, The Children's Hospital of Zhejiang University School of Medicine, Hangzhou, China.

Abstract

Nephronophthisis-like nephropathy-1 (NPHPL1) is a rare ciliopathy, caused by mutations of XPNPEP3. Despite a well-described monogenic etiology, the pathogenesis of XPNPEP3 associated with mitochondrial and ciliary function remains elusive. Here, we identified novel compound heterozygous mutations in NPHPL1 patients with renal lesion only or with extra bone cysts together. Patient-derived lymphoblasts carrying c.634G>A and c.761G>T together exhibit elevated mitochondrial XPNPEP3 levels via the reduction of mRNA degradation, leading to mitochondrial dysfunction in both urine tubular epithelial cells and lymphoblasts from patient. Mitochondrial XPNPEP3 was co-immunoprecipitated with respiratory chain complex I and was required for the stability and activity of complex I. Deletion of Xpnpep3 in mice resulted in lower activity of complex I, elongated primary cilium, and predisposition to tubular dilation and fibrosis under stress. Our findings provide valuable insights into the mitochondrial functions involved in the pathogenesis of NPHP.

Keywords: cell biology; disease; human Genetics.