# Mitochondrial fission surveillance is coupled to Caenorhabditis elegans DNA and chromosome segregation integrity

## TL;DR

This study identifies genes that regulate mitochondrial fission in C. elegans and reveals a new role for the DNA damage sensor ATR in maintaining mitochondrial function during chromosome segregation.

## Contribution

A novel screening method for mitochondrial fission regulators and the discovery of ATR's role in surveilling mitochondrial fission during chromosome segregation.

## Key findings

- RNAi screens identified 14 genes, including 3 kinases, that regulate mitochondrial fission in C. elegans.
- Chromosome missegregation and genome instability lead to mitochondrial fission dysregulation, independent of DRP-1.
- ATR (ATL-1 in C. elegans) helps mitigate mitochondrial fission defects caused by chromosome segregation errors.

## Abstract

Mitochondrial fission and fusion are tightly regulated to specify mitochondrial abundance, localization, and arrangement during cell division as well as in the diverse differentiated cell types and physiological states. However, the regulatory pathways for such mitochondrial dynamics are less explored than the mitochondrial fission and fusion components. Here we report a large-scale screen for genes that regulate mitochondrial fission. Mitochondrial fission defects cause a characteristic uneven fluorescent pattern in embryos carrying mitochondrial stress reporter genes. Using this uneven activation, we performed RNAi screens that identified 3 kinase genes from a ~ 500-kinase library and another 11 genes from 3,300 random genes that function in mitochondrial fission. Many of these identified genes play roles in chromosome segregation. We found that chromosome missegregation and genome instability lead to dysregulation of mitochondrial fission, possibly independent of DRP-1. ATL-1, the C. elegans ATR orthologue, plays a potentially protective role in alleviating the mitochondrial fission defect caused by chromosome missegregation. This establishes a screening paradigm for identifying mitochondrial fission regulators, which reveals the potential role of ATR in surveilling mitochondrial fission to mitigate dysregulation caused by improper chromosome segregation.

Mitochondrial dynamics is critical to the organelle’s functionality. The imbalance of mitochondrial fission and fusion is implicated in a variety of human diseases, including cancer, cardiovascular diseases, metabolic syndromes, and neurodegenerative disorders. Therefore, identifying the genes and mechanisms that regulate mitochondrial dynamics is of paramount importance. Traditionally, studies on mitochondrial dynamics have relied heavily on high-resolution imaging of mitochondrial morphology, which presents challenges for conducting large-scale genetic screens. In this study, we report a readily observable phenotype that is closely associated with defects in mitochondrial fission. Based on this phenotype, we establish a screening paradigm for identifying genes involved in mitochondrial fission. Through two RNA interference screens, we have identified several new genes functioning in chromosome segregation that also play a role in regulating mitochondrial fission. Furthermore, our work reveals a potential new role for the DNA damage sensor kinase ATR in surveilling mitochondrial fission and maintaining mitochondrial function in response to improper chromosome segregation. These findings illuminate a previously unrecognized mechanism through which the nucleus communicates with and regulates mitochondrial activity.