Disruption of mitochondrial functions involving mitochondrial permeability transition pore opening caused by maleic acid in rat kidney.

IF 4.6 Q2 MATERIALS SCIENCE, BIOMATERIALS
Ana Cristina Roginski, Ângela Beatris Zemniaçak, Rafael Aguiar Marschner, Simone Magagnin Wajner, Rafael Teixeira Ribeiro, Moacir Wajner, Alexandre Umpierrez Amaral
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引用次数: 3

Abstract

Propionic acid (PA) predominantly accumulates in tissues and biological fluids of patients affected by propionic acidemia that may manifest chronic renal failure along development. High urinary excretion of maleic acid (MA) has also been described. Considering that the underlying mechanisms of renal dysfunction in this disorder are poorly known, the present work investigated the effects of PA and MA (1-5 mM) on mitochondrial functions and cellular viability in rat kidney and cultured human embryonic kidney (HEK-293) cells. Mitochondrial membrane potential (∆ψm), NAD(P)H content, swelling and ATP production were measured in rat kidney mitochondrial preparations supported by glutamate or glutamate plus malate, in the presence or absence of Ca2+. MTT reduction and propidium iodide (PI) incorporation were also determined in intact renal cells pre-incubated with MA or PA for 24 h. MA decreased Δψm and NAD(P)H content and induced swelling in Ca2+-loaded mitochondria either respiring with glutamate or glutamate plus malate. Noteworthy, these alterations were fully prevented by cyclosporin A plus ADP, suggesting the involvement of mitochondrial permeability transition (mPT). MA also markedly inhibited ATP synthesis in kidney mitochondria using the same substrates, implying a strong bioenergetics impairment. In contrast, PA only caused milder changes in these parameters. Finally, MA decreased MTT reduction and increased PI incorporation in intact HEK-293 cells, indicating a possible association between mitochondrial dysfunction and cell death in an intact cell system. It is therefore presumed that the MA-induced disruption of mitochondrial functions involving mPT pore opening may be involved in the chronic renal failure occurring in propionic acidemia.

Abstract Image

马来酸对大鼠肾脏线粒体通透性转移孔打开等功能的破坏。
丙酸(PA)主要积聚在丙酸血症患者的组织和生物体液中,随着发育可能表现为慢性肾功能衰竭。高尿排泄马来酸(MA)也有描述。考虑到这种疾病中肾功能障碍的潜在机制尚不清楚,本研究研究了PA和MA (1-5 mM)对大鼠肾脏和培养的人胚胎肾(HEK-293)细胞线粒体功能和细胞活力的影响。在Ca2+存在或不存在的情况下,测定了谷氨酸或谷氨酸加苹果酸支持的大鼠肾线粒体制剂的线粒体膜电位(∆ψm)、NAD(P)H含量、肿胀和ATP产量。在与MA或PA预孵育24小时的完整肾细胞中,MTT减少和碘化丙啶(PI)掺入也被测定。MA降低Δψm和NAD(P) h含量,并诱导Ca2+负荷线粒体在用谷氨酸或谷氨酸加苹果酸呼吸时肿胀。值得注意的是,环孢素A加ADP完全阻止了这些改变,这表明线粒体通透性转变(mPT)参与其中。MA还显著抑制了使用相同底物的肾线粒体的ATP合成,这意味着强烈的生物能量损伤。相比之下,PA只引起这些参数的轻微变化。最后,在完整的HEK-293细胞中,MA减少了MTT的减少,增加了PI的掺入,这表明在完整的细胞系统中,线粒体功能障碍与细胞死亡之间可能存在关联。因此,推测ma诱导的线粒体功能破坏(包括mPT孔打开)可能与丙酸血症中发生的慢性肾功能衰竭有关。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
ACS Applied Bio Materials
ACS Applied Bio Materials Chemistry-Chemistry (all)
CiteScore
9.40
自引率
2.10%
发文量
464
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