Scholarlink

<p>The objective of the present review is to discuss the involvement of altered mitochondrial quality control in Mn-induced neurotoxicity. Existing data demonstrate that mitochondrial autophagy (mitophagy) and brain mitochondrial unfolded protein response (mtUPR) are activated in response to Mn exposure to counteract the Mn-induced mitochondrial dysfunction. Both mitophagy and mtUPR have significant overlap and mechanistic intersections with the integrated stress response (ISR). Increased Mn exposures impair mitochondrial dynamics, further aggravating Mn-induced mitochondrial dysfunction. Specifically, Mn suppresses PTEN-induced kinase 1 (PINK1)-Parkin-dependent mitophagy through a variety of mechanisms, including nitric oxide synthase 2 (NOS2)-dependent PINK1 S-nitrosylation, inhibition of transcription factor EB (TFEB) signaling, and mammalian target of rapamycin complex 1 (mTORC1) activation. In addition, Mn promotes mitochondrial fission by up-regulating dynamin-1-like protein (Drp1) expression and phosphorylation via the activation of c-Jun N-terminal kinase (JNK) and inhibition of sirtuin 1 (SIRT1)/peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) pathways. Concomitantly, Mn impairs mitochondrial fusion by inhibiting mitofusin (Mfn) 1/2 and dynamin-like 120&#xa0;kDa protein (Opa1) expression, leading to a reduction in mitochondrial size and disruption of the mitochondrial network. High-dose Mn exposure results in inhibition of peroxisome proliferator-activated receptor gamma coactivator 1α (PGC-1α)/nuclear factor erythroid 2-related factor 2 (NRF2)-dependent mitochondrial biogenesis. The latter may be mediated by inhibition of SIRT1/SIRT3 activity, as well as modulation of PINK1/ zinc finger protein 746 (ZNF746)/PGC-1α axis. Alterations in the mitochondrial quality control system may contribute to Mn-induced neuronal damage and neuroinflammation, indicating that dysregulation of the brain mitochondrial dynamics is an important mechanism by which Mn induces its neurotoxicity.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

The Role of Mitochondrial Quality Control in Manganese-induced Neurotoxicity

  • 期刊论文

  • 发表日期：

    2025年12月27日

查看全文
  • Alexey A. Tinkov,
  • Hyunjin Kim,
  • Anatoly V. Skalny,
  • Jung-Su Chang,
  • Abel Santamaria,
  • Rongzhu Lu,
  • Ji-Chang Zhou,
  • Aaron B. Bowman,
  • Eun-Sook Lee,
  • Yousef Tizabi,
  • Michael Aschner

摘要

The objective of the present review is to discuss the involvement of altered mitochondrial quality control in Mn-induced neurotoxicity. Existing data demonstrate that mitochondrial autophagy (mitophagy) and brain mitochondrial unfolded protein response (mtUPR) are activated in response to Mn exposure to counteract the Mn-induced mitochondrial dysfunction. Both mitophagy and mtUPR have significant overlap and mechanistic intersections with the integrated stress response (ISR). Increased Mn exposures impair mitochondrial dynamics, further aggravating Mn-induced mitochondrial dysfunction. Specifically, Mn suppresses PTEN-induced kinase 1 (PINK1)-Parkin-dependent mitophagy through a variety of mechanisms, including nitric oxide synthase 2 (NOS2)-dependent PINK1 S-nitrosylation, inhibition of transcription factor EB (TFEB) signaling, and mammalian target of rapamycin complex 1 (mTORC1) activation. In addition, Mn promotes mitochondrial fission by up-regulating dynamin-1-like protein (Drp1) expression and phosphorylation via the activation of c-Jun N-terminal kinase (JNK) and inhibition of sirtuin 1 (SIRT1)/peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) pathways. Concomitantly, Mn impairs mitochondrial fusion by inhibiting mitofusin (Mfn) 1/2 and dynamin-like 120 kDa protein (Opa1) expression, leading to a reduction in mitochondrial size and disruption of the mitochondrial network. High-dose Mn exposure results in inhibition of peroxisome proliferator-activated receptor gamma coactivator 1α (PGC-1α)/nuclear factor erythroid 2-related factor 2 (NRF2)-dependent mitochondrial biogenesis. The latter may be mediated by inhibition of SIRT1/SIRT3 activity, as well as modulation of PINK1/ zinc finger protein 746 (ZNF746)/PGC-1α axis. Alterations in the mitochondrial quality control system may contribute to Mn-induced neuronal damage and neuroinflammation, indicating that dysregulation of the brain mitochondrial dynamics is an important mechanism by which Mn induces its neurotoxicity.