The Role of Mitochondrial Quality Control in Manganese-induced Neurotoxicity

Alexey A Tinkov^{1

2

3}, Hyunjin Kim⁴, Anatoly V Skalny^{5

6}, Jung-Su Chang⁷, Abel Santamaria⁸, Rongzhu Lu⁹, Ji-Chang Zhou¹⁰, Aaron B Bowman⁴, Eun-Sook Lee¹¹, Yousef Tizabi¹², Michael Aschner¹³

Affiliations

¹ Institute of Bioelementology, Orenburg State University, 460018, Orenburg, Russia. tinkov.a.a@gmail.com.
² Center of Bioelementology and Human Ecology, Sechenov First Moscow State Medical University, 119146, Moscow, Russia. tinkov.a.a@gmail.com.
³ Laboratory of Ecobiomonitoring and Quality Control, Yaroslavl State University, 150003, Yaroslavl, Russia. tinkov.a.a@gmail.com.
⁴ School of Health Sciences, Purdue University, IN, 47907-2051, West Lafayette, USA.
⁵ Institute of Bioelementology, Orenburg State University, 460018, Orenburg, Russia.
⁶ Center of Bioelementology and Human Ecology, Sechenov First Moscow State Medical University, 119146, Moscow, Russia.
⁷ School of Nutrition and Health Sciences, Graduate Institute of Metabolism and Obesity Sciences, College of Nutrition, Taipei Medical University, 11031, Taipei, Taiwan.
⁸ Laboratorio de Nanotecnología y Nanomedicina, Departamento de Atención a la Salud, Universidad Autónoma Metropolitana-Xochimilco, and Facultad de Ciencias, Universidad Nacional Autónoma de México, 04960, Mexico City, Mexico.
⁹ Department of Preventive Medicine and Public Health Laboratory Sciences, School of Medicine, Jiangsu University, Jiangsu, 212013, Zhenjiang, China.
¹⁰ School of Public Health (Shenzhen), Shenzhen Campus of Sun Yat-sen University, 518107, Shenzhen, China.
¹¹ Department of Pharmaceutical Sciences, Florida A&M University, FL, 32307, Tallahassee, USA.
¹² Department of Pharmacology, Howard University College of Medicine, 20059, Washington, DC, USA.
¹³ Department of Molecular Pharmacology, Albert Einstein College of Medicine, NY, 10461, Bronx, USA. michael.aschner@einsteinmed.edu.

PMID: 41454179
DOI: 10.1007/s12640-025-00776-w

Review

The Role of Mitochondrial Quality Control in Manganese-induced Neurotoxicity

Alexey A Tinkov et al. Neurotox Res. 2025.

. 2025 Dec 27;44(1):2.

doi: 10.1007/s12640-025-00776-w.

Authors

Affiliations

¹ Institute of Bioelementology, Orenburg State University, 460018, Orenburg, Russia. tinkov.a.a@gmail.com.
² Center of Bioelementology and Human Ecology, Sechenov First Moscow State Medical University, 119146, Moscow, Russia. tinkov.a.a@gmail.com.
³ Laboratory of Ecobiomonitoring and Quality Control, Yaroslavl State University, 150003, Yaroslavl, Russia. tinkov.a.a@gmail.com.
⁴ School of Health Sciences, Purdue University, IN, 47907-2051, West Lafayette, USA.
⁵ Institute of Bioelementology, Orenburg State University, 460018, Orenburg, Russia.
⁶ Center of Bioelementology and Human Ecology, Sechenov First Moscow State Medical University, 119146, Moscow, Russia.
⁷ School of Nutrition and Health Sciences, Graduate Institute of Metabolism and Obesity Sciences, College of Nutrition, Taipei Medical University, 11031, Taipei, Taiwan.
⁸ Laboratorio de Nanotecnología y Nanomedicina, Departamento de Atención a la Salud, Universidad Autónoma Metropolitana-Xochimilco, and Facultad de Ciencias, Universidad Nacional Autónoma de México, 04960, Mexico City, Mexico.
⁹ Department of Preventive Medicine and Public Health Laboratory Sciences, School of Medicine, Jiangsu University, Jiangsu, 212013, Zhenjiang, China.
¹⁰ School of Public Health (Shenzhen), Shenzhen Campus of Sun Yat-sen University, 518107, Shenzhen, China.
¹¹ Department of Pharmaceutical Sciences, Florida A&M University, FL, 32307, Tallahassee, USA.
¹² Department of Pharmacology, Howard University College of Medicine, 20059, Washington, DC, USA.
¹³ Department of Molecular Pharmacology, Albert Einstein College of Medicine, NY, 10461, Bronx, USA. michael.aschner@einsteinmed.edu.

PMID: 41454179
DOI: 10.1007/s12640-025-00776-w

Abstract

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.

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Conflict of interest statement

Declarations. Ethics Approval: This is a review study. The Orenburg State University Ethics Committee has confirmed that no ethical approval is required. Consent To Participate: Not applicable. Consent To Publish: Not applicable. Competing interests: The authors declare no competing interests.

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The Role of Mitochondrial Quality Control in Manganese-induced Neurotoxicity

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The Role of Mitochondrial Quality Control in Manganese-induced Neurotoxicity

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