Long-read sequencing-based atlas of tissue-specific expression of Drp1 transcript variants

Authors:
  • FYFeng Yan
    Feng Yan
  • JJJafar S. Jabbari
    Jafar S. Jabbari
  • NLNaomi X.Y. Ling
    Naomi X.Y. Ling
  • AKAnne M. Kong
    Anne M. Kong
  • JTJia Q Truong
    Jia Q Truong
  • ARAyeshah A. Rosdah
    Ayeshah A. Rosdah
  • CLChristopher Langendorf
    Christopher Langendorf
  • LZLifang Zhang
    Lifang Zhang
  • JLJarmon G. Lees
    Jarmon G. Lees
  • SBSebastian Bass-Stringer
    Sebastian Bass-Stringer
  • DODanise Ann Onda
    Danise Ann Onda
  • KLKim Loh
    Kim Loh
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Abstract
Dynamin-related protein 1 (Drp1), encoded by DNM1L , is essential for mitochondrial fission, but its functional roles remain unclear due to isoform-specific effects from alternative splicing. Short-read RNA sequencing fails to resolve full-length isoforms involving distant exons, limiting our understanding. Here, we applied targeted long-read sequencing to profile full-length DNM1L transcripts in human left ventricle and iPSC-derived cardiomyocytes, recovering all annotated isoforms with conserved expression patterns and isoforms 1-4 being most abundant. Functional assays revealed that isoform abundance does not predict enzymatic activity. Extending this to six mouse tissues, we identified distinct, tissue-enriched expression profiles. Functional rescue in Drp1-knockout mouse embryonic fibroblasts showed isoform-dependent differences in mitochondrial fission. Isoforms lacking the A-insert (e.g., b and d) robustly rescued fission, while isoforms enriched in brain or muscle showed only partial rescue, suggesting exons 2 and 3 negatively regulate Drp1 activity. Our cross-species atlas integrates long-read transcriptomics with functional validation, revealing how isoform diversity underpins tissue-specific mitochondrial dynamics and physiological roles of Drp1. Summary: Using long-read sequencing, we mapped full-length DNM1L/Dnm1l isoforms in human and mouse tissues, uncovering tissue-specific expression and isoform-dependent mitochondrial fission activity. This reveals how alternative splicing shapes Drp1 function, with implications for understanding its role in health and disease.
Funding Information
  • Stafford Fox Medical Research Foundation

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