Abstract
Mitochondrial DNA (mtDNA) maintenance is essential to sustain a functionally healthy population of mitochondria within cells. Proper mtDNA replication and distribution within mitochondrial networks are essential to maintain mitochondrial homeostasis. However, the fundamental basis of mtDNA segregation and distribution within mitochondrial networks is still unclear. To address these questions, we developed an algorithm, Mitomate tracker to unravel the global distribution of nucleoids within mitochondria. Using this tool, we decipher the semi-regular spacing of nucleoids across mitochondrial networks. Furthermore, we show that mitochondrial fission actively regulates mtDNA distribution by controlling the distribution of nucleoids within mitochondrial networks. Specifically, we found that primary cells bearing disease-associated mutations in the fission proteins DRP1 and MYH14 show altered nucleoid distribution, and acute enrichment of enlarged nucleoids near the nucleus. Further analysis suggests that the altered nucleoid distribution observed in the fission mutants is the result of both changes in network structure and nucleoid density. Thus, our study provides novel insights into the role of mitochondria fission in nucleoid distribution and the understanding of diseases caused by fission defects.
Highlights
Results suggest that mitochondrial fission is required for nucleoid segregation, it remains unclear how fission contributes to nucleoid maintenance and the spatial distribution of nucleoids within mitochondrial networks
Mitochondrial function depends on the proper maintenance of mitochondrial DNA (mtDNA) and its distribution across the mitochondrial networks
While mitochondrial fusion plays an important role in mtDNA m aintenance[25], the role of mitochondrial fission in this process remains poorly understood
Summary
Results suggest that mitochondrial fission is required for nucleoid segregation, it remains unclear how fission contributes to nucleoid maintenance and the spatial distribution of nucleoids within mitochondrial networks. A small number of studies have previously measured nucleoid distribution using custom scripts on manually annotated images[14,15,16,17,18] These studies reported either the overall nucleoid density or the average distance between the two closest nucleoids (nearest neighbor distance; nndist), sometimes calculated without considering the positional constraints imposed by the mitochondrial n etwork[14,15]. We have developed Mitomate Tracker, an automated tool that evaluates the distribution of nucleoids within mitochondrial networks using both nndist and pcf Using this tool, we demonstrate that nucleoids are distributed in a semi regular fashion within mitochondrial networks, maintaining a minimal spacing between each other. These features were affected by mutations in MYH14 or DRP1, indicating that mitochondrial fission plays an important role in nucleoid distribution and maintenance
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