急性肾损伤
线粒体
化学
过氧化物酶体增殖物激活受体
肾
顺铂
β氧化
生物化学
药理学
生物
细胞生物学
脂肪酸
医学
受体
内科学
内分泌学
化疗
作者
Babu J. Padanilam,Mi Ra Noh,Ligyeom Ha,Jinu Kim,Hee‐Seong Jang
标识
DOI:10.1096/fasebj.2020.34.s1.06393
摘要
Objective Kidney is a highly metabolic organ and ATP depletion is critical to acute kidney injury (AKI). Mitochondrial fatty acid oxidation (FAO) is the preferred energy source of the kidney and is inhibited during AKI. A pivotal role for the mitochondrial matrix protein cyclophilin D (CypD) in regulating overall energy metabolism is being unraveled. We hypothesize that mitochondrial interaction between CypD and PPARα in renal proximal tubule (PT) where is highly susceptible to acute stimuli modulates FAO in cisplatin‐induced AKI (cisplatin AKI). Methods Using genetic and pharmacological intervention and protein‐protein interaction studies, we investigated whether PT‐CypD modulates FAO in cisplatin AKI through mitochondrial CypD‐PPARα binding and its sequestration. Results Cisplatin injury resulted in histological and functional damage in the kidney, along with downregulated mitochondrial FAO, increased intrarenal lipid accumulation and declined ATP level. However, PT‐specific deletion of CypD protected the malevolent effects. Immunoprecipitation and BioID methods demonstrated mitochondrial translocation of PPARα and its binding to CypD and sequestration. This led to inhibition of nuclear translocation of PPARα and reduced transcription of FAO genes during cisplatin AKI. Genetic or pharmacological inhibition of CypD suppressed mitochondrial CypD‐PPARα binding in cisplatin AKI, preventing the impairment of FAO and intracellular lipid accumulation. Conclusions These results uncover a novel mechanism by which mitochondrial interaction between CypD and PPARα impairs FAO in cisplatin AKI. Targeting their interaction may be a potential therapeutic strategy to prevent energy depletion and cell death in AKI. Support or Funding Information This work was supported by NIH grants DK‐116987, DK‐120533 and American Heart Association (AHA) Grant in Aid 15GRNT25080031 (BJP), AHA postdoctoral fellowship Grant 15POST25130003 (HSJ), and grants (NRF‐2016R1C1B2012080 and NRF‐2019R1F1A1041410) from the National Research Foundation of Korea (JK).
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