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Background <p>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.</p> Methods <p>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.</p> Results <p>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.</p> Conclusions <p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月8日

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  • Yun Teng,
  • Chao Luo,
  • Qingbo Xu,
  • Jingyao Mu,
  • Lucy Teng,
  • Hongjia Qian,
  • Yinan Huang,
  • Minmin Liu,
  • Lifeng Zhang,
  • Juw Won Park,
  • Jae Yeon Hwang,
  • Maiying Kong,
  • Jun Yan,
  • Michael L. Merchant,
  • Huang-Ge Zhang

摘要

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.