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      Upregulation of TIPE1 in tubular epithelial cell aggravates diabetic nephropathy by disrupting PHB2 mediated mitophagy

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          Abstract

          Renal tubular epithelial cells (RTECs) are one of the most mitochondria-rich cell types, and are thus vulnerable to mitochondrial dysregulation, which is defined as a pivotal event in tubular damage in diabetic nephropathy (DN). However, the underlying mechanisms remain largely unknown. Here, we investigated the role and mechanisms of tumor necrosis factor alpha-induced protein 8-like 1 (TNFAIP8L1/TIPE1) in high glucose (HG)-induced mitochondrial dysfunction in RTECs and DN progression. TIPE1 expression was predominantly upregulated in RTECs in patients with DN and mice with streptozotocin (STZ)-induced DN. Conditional knockout of Tipe1 in RTECs significantly decreased the urine protein creatinine ratio, renal tubular damage, epithelial-mesenchymal transition, and interstitial fibrosis in STZ-induced mice. RNA sequencing revealed that citrate cycle-related genes were positively enriched in the renal tissues of RTEC-specific Tipe1 knockout mice. Tipe1 deficiency upregulated ATP levels, mitochondrial membrane potential, and respiration rate, but downregulated mitochondrial ROS levels in RTECs. Furthermore, Tipe1 ablation led to enhanced mitophagy in RTECs, indicative of increased LC3II, PINK1, and Parkin expression, but decreased p62 expression in mitochondria. Mechanistically, mass spectrometry screening and co-immunoprecipitation assays revealed the interaction of TIPE1 with prohibitin 2 (PHB2), a crucial mitophagy receptor. Intriguingly, TIPE1 promoted the ubiquitination and proteasomal degradation of PHB2. Subsequently, PHB2 knockdown almost abrogated the improvement of Tipe1 loss on HG-induced tubular cell mitophagy and damage. Thus, TIPE1 disrupts mitochondrial homeostasis in RTECs and promotes tubular damage by destabilizing PHB2 under HG conditions. Hence, TIPE1 may act as a potential therapeutic target to prevent DN progression.

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          Highlights

          • •

            TIPE1 is highly expressed in RTECs of DN.

          • •

            TIPE1 aggravates diabetic renal injury and fibrosis.

          • •

            TIPE1 disrupts the mitochondria homeostasis of RTECs by inhibiting mitophagy.

          • •

            TIPE1 interacts with and promotes the proteasomal degradation of PHB2.

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          Mitochondria as multifaceted regulators of cell death

          Florian J. Bock, Stephen Tait (2019)
          Through their many and varied metabolic functions, mitochondria power life. Paradoxically, mitochondria also have a central role in apoptotic cell death. Upon induction of mitochondrial apoptosis, mitochondrial outer membrane permeabilization (MOMP) usually commits a cell to die. Apoptotic signalling downstream of MOMP involves cytochrome c release from mitochondria and subsequent caspase activation. As such, targeting MOMP in order to manipulate cell death holds tremendous therapeutic potential across different diseases, including neurodegenerative diseases, autoimmune disorders and cancer. In this Review, we discuss new insights into how mitochondria regulate apoptotic cell death. Surprisingly, recent data demonstrate that besides eliciting caspase activation, MOMP engages various pro-inflammatory signalling functions. As we highlight, together with new findings demonstrating cell survival following MOMP, this pro-inflammatory role suggests that mitochondria-derived signalling downstream of pro-apoptotic cues may also have non-lethal functions. Finally, we discuss the importance and roles of mitochondria in other forms of regulated cell death, including necroptosis, ferroptosis and pyroptosis. Collectively, these new findings offer exciting, unexplored opportunities to target mitochondrial regulation of cell death for clinical benefit.
          Article 0 comments Cited 715 times – based on 0 reviews     Review now
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            Prohibitin 2 Is an Inner Mitochondrial Membrane Mitophagy Receptor.

            Yongjie Wei, Wei-Chung Chiang, Rhea Sumpter … (2017)
            The removal of unwanted or damaged mitochondria by autophagy, a process called mitophagy, is essential for key events in development, cellular homeostasis, tumor suppression, and prevention of neurodegeneration and aging. However, the precise mechanisms of mitophagy remain uncertain. Here, we identify the inner mitochondrial membrane protein, prohibitin 2 (PHB2), as a crucial mitophagy receptor involved in targeting mitochondria for autophagic degradation. PHB2 binds the autophagosomal membrane-associated protein LC3 through an LC3-interaction region (LIR) domain upon mitochondrial depolarization and proteasome-dependent outer membrane rupture. PHB2 is required for Parkin-induced mitophagy in mammalian cells and for the clearance of paternal mitochondria after embryonic fertilization in C. elegans. Our findings pinpoint a conserved mechanism of eukaryotic mitophagy and demonstrate a function of prohibitin 2 that may underlie its roles in physiology, aging, and disease.
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              Molecular mechanisms and physiological functions of mitophagy

              Mashun Onishi, Koji Yamano, Miyuki Sato … (2021)
              Abstract Degradation of mitochondria via a selective form of autophagy, named mitophagy, is a fundamental mechanism conserved from yeast to humans that regulates mitochondrial quality and quantity control. Mitophagy is promoted via specific mitochondrial outer membrane receptors, or ubiquitin molecules conjugated to proteins on the mitochondrial surface leading to the formation of autophagosomes surrounding mitochondria. Mitophagy‐mediated elimination of mitochondria plays an important role in many processes including early embryonic development, cell differentiation, inflammation, and apoptosis. Recent advances in analyzing mitophagy in vivo also reveal high rates of steady‐state mitochondrial turnover in diverse cell types, highlighting the intracellular housekeeping role of mitophagy. Defects in mitophagy are associated with various pathological conditions such as neurodegeneration, heart failure, cancer, and aging, further underscoring the biological relevance. Here, we review our current molecular understanding of mitophagy, and its physiological implications, and discuss how multiple mitophagy pathways coordinately modulate mitochondrial fitness and populations.
              Article 0 comments Cited 345 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Xiaohong Liang
                Journal
                Journal ID (nlm-ta): Redox Biol
                Journal ID (iso-abbrev): Redox Biol
                Title: Redox Biology
                Publisher: Elsevier
                ISSN (Electronic): 2213-2317
                Publication date PMC-release: 07 February 2022
                Publication date Collection: April 2022
                Publication date (Electronic): 07 February 2022
                Volume: 50
                Electronic Location Identifier: 102260
                Affiliations
                [a ]Key Laboratory for Experimental Teratology of Ministry of Education and Department of Immunology, School of Basic Medical Sciences, Cheeloo Medical College, Shandong University, Jinan, Shandong, China
                [b ]Department of Nephropathy, Qilu Hospital of Shandong University, Cheeloo Medical College, Shandong University, Jinan, Shandong, Jinan, Shandong, PR China
                [c ]Shandong Collaborative Innovation Center of Technology and Equipment for Biological Diagnosis and Therapy, Jinan, Shandong, China
                Author notes
                [∗ ]Corresponding author. Key Laboratory for Experimental Teratology of Ministry of Education and Department of Immunology; School of Basic Medical Sciences, Cheeloo Medical College, Shandong University, Jinan, 250012, China. liangxiaohong@ 123456email.sdu.edu.cn
                [∗∗ ]Corresponding author. Department of Nephropathy, Qilu Hospital of Shandong University; Cheeloo Medical College, Shandong University, Jinan, 250000, China.
                Article
                Publisher Item ID: S2213-2317(22)00032-5 Publisher ID: 102260
                DOI: 10.1016/j.redox.2022.102260
                PMC ID: 8844679
                PubMed ID: 35152003
                SO-VID: 9facc52c-96c0-4f25-acd5-f8f2355450d5
                Copyright © © 2022 The Authors
                License:

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                Date received : 5 January 2022
                Date revision received : 1 February 2022
                Date accepted : 4 February 2022
                Categories
                Subject: Research Paper

                Keywords: diabetic nephropathy,renal tubular epithelial cells,tipe1,mitophagy,phb2,rtec, renal tubular epithelial cell,dn, diabetic nephropathy,tnfaip8l1/tipe1, tumor necrosis factor alpha-induced protein 8-like 1
                Data availability:
                Keywords: diabetic nephropathy, renal tubular epithelial cells, tipe1, mitophagy, phb2, rtec, renal tubular epithelial cell, dn, diabetic nephropathy, tnfaip8l1/tipe1, tumor necrosis factor alpha-induced protein 8-like 1

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