Plant-derived mitochondria mitigate aging-related neurodegeneration by reprogramming microglial mitochondrial energy metabolism.

Overview

1. Brown Cancer Center, Department of Medicine, University of Louisville School of Medicine, CTRB Room 309, 505 S. Hancock Street, Louisville, KY 40202 USA
2. Department of Central Laboratory, The Affiliated Huai’an First People’s Hospital of Nanjing Medical University, Huai’an, 223300 Jiangsu China
3. Department of Microbiology and Immunology, University of Louisville, Louisville, KY USA
4. Massachusetts Institute of Technology, Cambridge, MA USA
5. Department of Breast and Thyroid Surgery, The Affiliated Huai’an First People’s Hospital of Nanjing Medical University, Huai’an, 223300 Jiangsu China
6. Department of Bioinformatics and Biostatistics, SPHIS, University of Louisville, Louisville, KY 40202 USA
7. Kidney Disease Program and Clinical Proteomics Center, University of Louisville, Louisville, KY USA
8. Robley Rex Veterans Affairs Medical Center, Louisville, KY 40206 USA

Abstract

Background: Intercellular mitochondrial transfer is pivotal in both healthy and pathological states. Supplementing healthy mitochondria is emerging as a promising therapeutic approach for various diseases. Non-immunogenic edible plants, which contain mitochondria, offer a novel avenue for such therapies.

Methods: Mitochondria were isolated from several commonly consumed edible plants (P-Mit) using differential centrifugation followed by sucrose gradient ultracentrifugation. The distribution of P-Mit, particularly in the brain, was examined with a mitochondrial membrane-potential dye and an imaging system. As a proof of concept, the molecular interactions underlying turmeric-derived mitochondria (T-Mit) uptake by microglia were elucidated through affinity precipitation coupled with mass spectrometry. By labeling with gold-nanoparticles in a distinct triangular or spherical shape followed by electron microscopy and energy dispersive spectroscopy analysis, we demonstrated the physical fusion of T-Mit and animal mitochondria in microglia. Mitochondrial functions such as superoxide levels, ATP-linked mitochondrial respiration, glycolysis and electron transport chain activity were assessed to determine the impact of T-Mit on aging-related microglial dysfunction. Next-generation small RNA sequencing revealed the underlying mechanism by which T-Mit-derived small RNAs modulate the expression of NADH dehydrogenase (ND) genes in microglia.

Results: Orally administered T-Mit travelled from the gut to the brain in aged male mice, where they fused with microglial mitochondria (M-Mit), reprogramming M-Mit energy metabolism and reversing aging-related cognitive dysfunction. Specifically, T-Mit was taken up by microglia via the phagocytic receptor TREM2. Subsequently, T-Mit fused with M-Mit in a mitofusin 1-dependent manner. The T-Mit microRNAs Tae-miR319 and Osa-miR166a-3p then integrated into M-Mit, inhibiting the expression of complex I subunits ND4 and ND5. This inhibition alleviated reverse electron transport (RET) at complex I, reducing reactive oxygen species (ROS) production and facilitating ATP production, ultimately rescuing aging-related cognitive decline. Data from elderly human subjects also showed overactivation of the RET process and overproduction of ROS, accompanied by low ATP levels in microglia.

Conclusions: Our findings fundamentally alter our understanding of the regulation of mammalian mitochondrial biology by P-Mit and may lead to P-Mit-based transfer therapy for preventing or treating human mitochondrial disorder-related diseases.

Supplementary Information: The online version contains supplementary material available at 10.1186/s40035-026-00565-1.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Data

Datasets cited

• geo:GSE165349, at NCBI GEO; found in “Data availability”

Data availability

All data generated or analyzed during this study are included in this published article and its Supplementary information files or provided in source data file. The microRNA sequencing data were deposited in the National Center for Biotechnology Information (NCBI) Gene Expression Omnibus (GEO) database with the accession number GSE165349 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE165349) (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE165349). The data that support the findings of this study are available on request from the corresponding author.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Version 1, 27 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 15 authors, 10 keywords, 9 MeSH terms, 2 funders, 135 references.

Cite

This paper

Teng, Y., Luo, C., Xu, Q., Mu, J., Teng, L., Qian, H., Huang, Y., Liu, M., Zhang, L., Park, J. W., Hwang, J. Y., Kong, M., Yan, J., Merchant, M. L., & Zhang, H.-G. (2026). Plant-derived mitochondria mitigate aging-related neurodegeneration by reprogramming microglial mitochondrial energy metabolism. Translational neurodegeneration, 15(1), 30. https://doi.org/10.1186/s40035-026-00565-1

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