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      Mitochondrial stress response gene Clpp deficiency impairs oocyte competence and deteriorate cyclophosphamide-induced ovarian damage in young mice

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          Abstract

          Chemotherapy is extensively used to treat cancers and is often associated with ovarian damage and leads to premature ovarian insufficiency and infertility, while the role of mitochondria during ovarian damage with chemotherapy remains unknown. This study used a mouse model with oocyte-specific deletion of mitochondrial stress response gene Caseinolytic peptidase P ( Clpp) to investigate mitochondrial homeostasis in oocytes from mice receiving a chemotherapeutic drug cyclophosphamide (CTX). We found that oocyte-specific deletion of Clpp reduced fecundity of the mice at advanced age. The deletion led to meiotic defects with elevated abnormal spindle rate and aneuploidy rate with impaired mitochondrial function in the MII oocytes from 8-week-old mice. Upon CTX treatment at 8-week-old, the oocyte competence and folliculogenesis from the oocyte-specific Clpp knockout mice was further deteriorated with dramatic impairment of mitochondrial distribution and function including elevated ROS level, decreased mitochondrial membrane potential, respiratory chain activity and ATP production. Taken together, the results indicate that that ClpP was required for oocyte competence during maturation and early folliculogenesis, and its deficiency deteriorate cyclophosphamide-induced ovarian damage.

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          This article provides an update on the global cancer burden using the GLOBOCAN 2020 estimates of cancer incidence and mortality produced by the International Agency for Research on Cancer. Worldwide, an estimated 19.3 million new cancer cases (18.1 million excluding nonmelanoma skin cancer) and almost 10.0 million cancer deaths (9.9 million excluding nonmelanoma skin cancer) occurred in 2020. Female breast cancer has surpassed lung cancer as the most commonly diagnosed cancer, with an estimated 2.3 million new cases (11.7%), followed by lung (11.4%), colorectal (10.0 %), prostate (7.3%), and stomach (5.6%) cancers. Lung cancer remained the leading cause of cancer death, with an estimated 1.8 million deaths (18%), followed by colorectal (9.4%), liver (8.3%), stomach (7.7%), and female breast (6.9%) cancers. Overall incidence was from 2-fold to 3-fold higher in transitioned versus transitioning countries for both sexes, whereas mortality varied <2-fold for men and little for women. Death rates for female breast and cervical cancers, however, were considerably higher in transitioning versus transitioned countries (15.0 vs 12.8 per 100,000 and 12.4 vs 5.2 per 100,000, respectively). The global cancer burden is expected to be 28.4 million cases in 2040, a 47% rise from 2020, with a larger increase in transitioning (64% to 95%) versus transitioned (32% to 56%) countries due to demographic changes, although this may be further exacerbated by increasing risk factors associated with globalization and a growing economy. Efforts to build a sustainable infrastructure for the dissemination of cancer prevention measures and provision of cancer care in transitioning countries is critical for global cancer control.
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              The complete sequence of the 16,569-base pair human mitochondrial genome is presented. The genes for the 12S and 16S rRNAs, 22 tRNAs, cytochrome c oxidase subunits I, II and III, ATPase subunit 6, cytochrome b and eight other predicted protein coding genes have been located. The sequence shows extreme economy in that the genes have none or only a few noncoding bases between them, and in many cases the termination codons are not coded in the DNA but are created post-transcriptionally by polyadenylation of the mRNAs.
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                Author and article information

                Contributors
                Journal
                Front Endocrinol (Lausanne)
                Front Endocrinol (Lausanne)
                Front. Endocrinol.
                Frontiers in Endocrinology
                Frontiers Media S.A.
                1664-2392
                24 March 2023
                2023
                : 14
                : 1122012
                Affiliations
                [1] 1 Department of Breast and Thyroid Surgery, Peking University Shenzhen Hospital , Shenzhen, China
                [2] 2 Shenzhen Key Laboratory of Fertility Regulation, Reproductive Medicine Center, The University of Hong Kong-Shenzhen Hospital , Shenzhen, China
                [3] 3 Department of Obstetrics and Gynaecology, The University of Hong Kong - Shenzhen Hospital , Shenzhen, China
                [4] 4 Department of Obstetrics and Gynaecology, Li Ka Shing Faculty of Medicine, The University of HongKong , Hong Kong, Hong Kong SAR, China
                Author notes

                Edited by: Gabriela Jaita, Instituto de Investigaciones Biomédicas, Universidad de Buenos Aires, Argentina

                Reviewed by: Yueqiu Tan, Institute of Reproductive and Stem Cell Engineering, Central South University, China; Silvana A. Andric, University of Novi Sad, Serbia

                *Correspondence: Tianren Wang, wtrcmu@ 123456126.com ; Chenxi Guo, guocx@ 123456hku-szh.org

                †These authors contributed equally to this work and share first authorship

                ‡These authors contributed equally to this work and share last authorship

                This article was submitted to Reproduction, a section of the journal Frontiers in Endocrinology

                Article
                10.3389/fendo.2023.1122012
                10081448
                37033217
                7b281133-0b03-4527-8e86-1532ff51abd3
                Copyright © 2023 Li, Gu, Zhou, Wu, Li, Hua, Hai, Xiao, Su, Yeung, Liu, Guo and Wang

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 12 December 2022
                : 28 February 2023
                Page count
                Figures: 5, Tables: 0, Equations: 0, References: 53, Pages: 13, Words: 7171
                Funding
                Funded by: National Natural Science Foundation of China , doi 10.13039/501100001809;
                This work was supported by the National Natural Science Foundation of China (No. 81971453); Shenzhen Fundamental Research Program, China (No. JCYJ20200109150429414); Shenzhen Science and Technology Program, China (No. RCYX20200714114705073, No. KQTD20190929172749226).
                Categories
                Endocrinology
                Original Research

                Endocrinology & Diabetes
                oocyte,follicle development,cyclophosphamide,mitochondria,clpp
                Endocrinology & Diabetes
                oocyte, follicle development, cyclophosphamide, mitochondria, clpp

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