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Defective Mitochondrial Dynamics Underlie Manganese-Induced Neurotoxicity

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Abstract

Perturbations in mitochondrial dynamics have been observed in most neurodegenerative diseases. Here, we focus on manganese (Mn)-induced Parkinsonism-like neurodegeneration, a disorder associated with the preferential of Mn in the basal ganglia where the mitochondria are considered an early target. Despite the extensive characterization of the clinical presentation of manganism, the mechanism by which Mn mediated mitochondrial toxicity is unclear. In this study we hypothesized whether Mn exposure alters mitochondrial activity, including axonal transport of mitochondria and mitochondrial dynamics, morphology, and network. Using primary neuron cultures exposed to 100 μM Mn (which is considered the threshold of Mn toxicity in vitro) and intraperitoneal injections of MnCl2 (25mg/kg) in rat, we observed that Mn increased mitochondrial fission mediated by phosphorylation of dynamin-related protein-1 at serine 616 (p-s616-DRP1) and decreased mitochondrial fusion proteins (MFN1 and MFN2) leading to mitochondrial fragmentation, defects in mitochondrial respiratory capacity, and mitochondrial ultrastructural damage in vivo and in vitro. Furthermore, Mn exposure impaired mitochondrial trafficking by decreasing dynactin (DCTN1) and kinesin-1 (KIF5B) motor proteins and increasing destabilization of the cytoskeleton at protein and gene levels. In addition, mitochondrial communication may also be altered by Mn exposure, increasing the length of nanotunnels to reach out distal mitochondria. These findings revealed an unrecognized role of Mn in dysregulation of mitochondrial dynamics providing a potential explanation of early hallmarks of the disorder, as well as a possible common pathway with neurological disorders arising upon chronic Mn exposure.

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Data Availability

The RNA-sequencing dataset generated during this study is available on NCBI GEO with the accession number GSE153017. All other data are available from the corresponding authors upon reasonable request.

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Acknowledgements

We are grateful to Vera DesMarais, Peng Guo, Andrea Briceno, Hillary Guzik, Timothy Mendez and Xheni Nishku from the Analytical Imaging Facility, Albert Einstein College of Medicine, for the invaluable help acquiring the images, the technical assistance, and their critical comments. We thank Xueliang Du for the technical support with the Seahorse measurements. Lastly, we would like to acknowledge Dr. Estela Area Gomez (Columbia University, NY) for critical reading of the manuscript.

Code Availability

Customized scripts generated for this study are available from the corresponding author on request.

Funding

This work was supported by the National Institute of Environmental Health Sciences R01-ES10563 grant to M.A. The microscopy images were acquired at the Analytical Imaging Facility of Albert Einstein College of Medicine, which was partially funded by NCI Cancer Center Support Grant P30CA013330. The Leica SP8 confocal microscope was purchased under the Shared Instrumentation Grant (SIG) 1S10OD023591-01 and the JEOL 1400 Plus transmission electron microscope, 1S10OD016214-01A1. O.M.I. was supported by the 2017 IBRO-ISN Research Fellowship.

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Authors and Affiliations

  1. Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY, USA

    Patricia Morcillo, Omamuyovwi M. Ijomone, Akinyemi Ayodele & Michael Aschner

  2. Columbia Center for Translational Immunology, Columbia University Medical Center, New York, NY, USA

    Hector Cordero

  3. The Neuro-Lab, School of Health and Health Technology, Federal University of Technology, Akure, Nigeria

    Omamuyovwi M. Ijomone

  4. Food Chemistry, Faculty of Mathematics and Natural Sciences, University of Wuppertal, Wuppertal, Germany

    Julia Bornhorst

  5. Analytical Imaging Facility, Albert Einstein College of Medicine, Bronx, NY, USA

    Leslie Gunther & Frank P. Macaluso

  6. School of Health Sciences, Purdue University, West Lafayette, IN, USA

    Aaron B. Bowman

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  1. Patricia Morcillo
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  2. Hector Cordero
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Contributions

P.M. and M.A. conceived the project. P.M., O.M.I., and A.A. designed and performed the in vivo experiment. J.B. performed ICP-MS measurements. H.C. performed RNA-seq analyses and prepared Fig. 6. F.P.M. and L.G. performed the AT-SEM studies. P.M. designed and performed the rest of the experiments, analyzed the data, developed analytical tools, and wrote the paper. A.B.B. and M.A. edited the manuscript and secured funding. All authors contributed to the final version of the manuscript.

Corresponding authors

Correspondence to Patricia Morcillo or Michael Aschner.

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Ethics Approval

All animal experiments were performed according to the Institutional Animal Care and Use Committees of Albert Einstein College of Medicine and conformed to the National Institutes of Health Guidelines for use of animals in research.

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The authors declare no competing interests.

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Supplementary Information

ESM 1

Supplemental Figure S1: Mn induces cytotoxicity in primary neuron culture in a dose- and time- dependent manner. Cell viability measured by MTT assay in primary neurons were treated with various concentrations of Mn (100, 500 and 1000 μM) for 1 h (green lines) and 24 h (pink lines). Values are normalized to the control and expressed as mean ± SD (n=5). Statistical significance was analyzed by one-way ANOVA and post-hoc Tukey test (p<0.05). Different lower-case letters indicate significant differences among dosages (control group contains a). Supplemental Figure S2: Mn exposure results in mitochondrial fragmentation in primary neurons. A) Representative confocal microscopy images showing mitochondrial morphology followed by mitochondrial morphological skeleton generated by Mitochondrial Network Analysis (MiNA) toolset in control and primary neurons exposed to 100 μM Mn for 1 h. In the representation of the skeleton, mitochondrial networks are represented in yellow and mitochondrial junction are represented in violet. Scale bars 5 μm. B-E) Quantification of number of individuals (B), networks (C), branches per network (D), or length of the branches (E) in control and Mn-exposed primary neuron culture (n=4 independent cultures with ≥ 15 neurons each). Results are expressed as mean ± SD. Statistical significance was analyzed by Student t-test (*p < 0.05; **p < 0.01; p < 0.01; ***p < 0.001, **** p < 0.0001). Supplemental Figure S3: Intraperitoneal Mn administration is accumulated in rat striatum and contributes to body weight changes: A) Intraperitoneal administration (ip) of MnCl2.4H2O (25 mg/kg) is accumulated in rat striatum measured by inductively coupled plasma mass spectrometry (ICP-MS). Bar represent Mn levels (mg/kg) in control and exposed striatum. Results are expressed as mean ± SD (n=6). B) Bars represent the body weight (g) at the beginning of the experiment (day 0) and after ip injection of vehicle (control) or Mn (day 16). Results are expressed as mean± SD (n=6). Statistical significance was analyzed by Student t-test (**p < 0. 01). Supplemental Figure S4: Analysis of morphological parameters of mitochondria from the neuropils and soma of striatum neurons. A-C) Frequency distribution of the area (A), perimeter (B) and circularity (C) of the mitochondria in the neuropils of striatum neurons from control and Mn-exposed groups (n=4). D-F) Frequency distribution of the area (D), perimeter (E) and circularity (F) of the mitochondria in the soma of striatum neurons from control and Mn-exposed groups (n=4). Supplemental Figure S5: Mitochondrial transport failure underlies Mn-induced neurotoxicity in vivo. Representative western blot of acetyl-K40-TUBA, KIF5B and DCTN1 in rat striatum exposed to Mn. TUBA and ACTB were used as a loading control for both control and Mn-exposed groups. (PDF 2020 kb)

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Morcillo, P., Cordero, H., Ijomone, O.M. et al. Defective Mitochondrial Dynamics Underlie Manganese-Induced Neurotoxicity. Mol Neurobiol 58, 3270–3289 (2021). https://doi.org/10.1007/s12035-021-02341-w

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