Abstract
ABSTRACTThe maintenance of mitochondrial respiratory function and homeostasis is essential to human health. Here, we identify condensin II subunits as novel regulators of mitochondrial respiration and mitochondrial stress responses. Condensin II is present in the nucleus and cytoplasm. While the effects of condensin II depletion on nuclear genome organization are well studied, the effects on essential cytoplasmic and metabolic processes are not as well understood. Excitingly, we observe that condensin II chromosome-associated protein (CAP) subunits individually localize to different regions of mitochondria, suggesting possible mitochondrial-specific functions independent from those mediated by the canonical condensin II holocomplex. Changes in cellular ATP levels and mitochondrial respiration are observed in condensin II CAP subunit-deficient cells. Surprisingly, we find that loss of NCAPD3 also sensitizes cells to oxidative stress. Together, these studies identify new, and possibly independent, roles for condensin II CAP subunits in preventing mitochondrial damage and dysfunction. These findings reveal a new area of condensin protein research that could contribute to the identification of targets to treat diseases where aberrant function of condensin II proteins is implicated.
Highlights
Condensin II subunits localize to mitochondria in human cells To test whether condensin II might localize to mitochondria in human cells, we first performed immunofluorescence analyses using primary antibodies to detect the α-subunit of complex V (ATP synthase; denoted CoV) and NCAPD3 in human colon adenocarcinoma (HT-29) cells induced to express non-targeting (NT) control short hairpin RNA or NCAPD3-specific shRNA (Fig. 1A) (Schuster et al, 2015)
An antibody directed against internal residues of NCAPD3-detected NCAPD3 protein in mitochondrial lysate of NT shRNA-expressing cells (Fig. 1B,C), and this signal decreased in mitochondrial lysate from cells expressing NCAPD3 shRNA, suggesting that the detected protein species was, NCAPD3
Our data demonstrate that the condensin II proteins NCAPD3, NCAPH2 and SMC2 localize to mitochondria
Summary
The condensin II complex, which is found in the nucleus and in the cytoplasm throughout the cell cycle, regulates DNA organization (Hirano, 2012, 2016; Kalitsis et al, 2017; Ono et al, 2004; Li et al, 2015a; Rowley et al, 2019; Bauer et al, 2012; Hartl et al, 2008; Joyce et al, 2012; Rosin et al, 2018) and maintains genome stability (Woodward et al, 2016). The complex consists of chromosome-associated protein (CAP) subunits including the kleisin NCAPH2, and the α-helical Huntingtin, elongation factor 3, PR65/A and TOR (HEAT)-repeat containing proteins, NCAPD3 and NCAPG2 (Nasmyth and Haering, 2005). The cytoplasmic organelles to which condensin II localizes, and the impacts of condensin II-mediated regulation of functions within those organelles have yet to be discovered
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