A synaptic mitochondrion–ribbon–vesicle complex organizes photoreceptor neurotransmission

Photoreceptor synapses rely on mitochondria, synaptic ribbons, and vesicles, yet how these elements integrate into functional units remains unclear. Here we show, using focused ion beam-scanning electron microscopy (FIB-SEM) and electrophysiology, that they form synaptic mitochondrion–ribbon–vesicle complexes (sMRVcs) with fundamentally different architectures in rods and cones. Rod spherules exhibit a strict 1:1 pairing of a single megamitochondrion with one ribbon, sustaining continuous glutamate release in darkness, whereas cone pedicles contain multiple distributed sMRVcs.

Disrupting the mitochondrial anchor protein syntaphilin shifts this ratio to 2:1 in rods, with additional mitochondria recruited near the ribbon, and enhances synaptic transmission. In a retinal degeneration model, the sMRVc progressively disassembles before functional decline, with fragmented mitochondria, detached ribbons, and dispersed vesicles. We also identify non-ribbon release sites selectively targeting horizontal cells.

These findings establish the sMRVc as a conserved structural–metabolic module whose subtype-specific organization reflects distinct visual demands and whose integrity is essential for synaptic health. Grimes, and Amurta Nath for valuable discussions and suggestions regarding the MCI formula. We are grateful to Wei Li and Yizhen Zhang for important suggestions on physiology experiments.

We thank Jiansheng Guo for his assistance with FIB‑SEM sample preparation at the Center of Cryo‑Electron Microscopy (CCEM), Zhejiang University. We are also grateful to Fei Sun, Xixia Li, Zhongshuang Lv, and Xiaoyun Zhang for acquiring FIB‑SEM images at the Center for Biological Imaging, Institute of Biophysics, Chinese Academy of Sciences (CAS); to Liqing Liu and Tianjiao Wang for image acquisition at the National Multimode Trans‑Scale Biomedical Imaging Center, the Interdisciplinary Center for Biointelligence and Center for Biological Imaging, and the Core Facility for Protein Science, Institute of Biophysics, CAS. We thank Xiaoqian Lai and Jia Li for their technical assistance.

This work was supported by grants from National Key Research and Development Program of China (2022YFA1105503); “1010” Program, Eye Hospital, Wenzhou Medical University (1010JZYJ202301); Start-up Foundation of Wenzhou Medical University (89219003). These authors contributed equally: Fenglan Wang, Wenna Zhao, Xin Lin, Xiaotian Bian, Qingwen Yang. State Key Laboratory of Eye Health, Eye Hospital, Wenzhou Medical University, Wenzhou, China Fenglan Wang, Wenna Zhao, Xin Lin, Xiaotian Bian, Qingwen Yang, Zhongqun Chen, Fang He, Xiaoqing Liu, Bilin Rao, Jia Qu & Jun Zhang Laboratory of Retinal Physiology and Disease, School of Ophthalmology and Optometry, Wenzhou Medical University, Wenzhou, China The authors declare no competing interests.

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