A threshold of transmembrane potential is required for mitochondrial dynamic balance mediated by DRP1 and OMA1

Authors

Edith Jones, The University of Texas Rio Grande Valley
Norma Gaytan, The University of Texas Rio Grande Valley
Iraselia Garcia, The University of Texas Rio Grande Valley
Alan Herrera, The University of Texas Rio Grande Valley
Manuel Ramos, The University of Texas Rio Grande Valley
Divya Agarwala, The University of Texas Rio Grande Valley
Maahrose Rana, The University of Texas Rio Grande Valley
Wendy Innis-Whitehouse, The University of Texas Rio Grande Valley
Erin Schuenzel, The University of Texas Rio Grande Valley
Robert Gilkerson, The University of Texas Rio Grande Valley

Document Type

Article

Publication Date

11-2016

Abstract

As an organellar network, mitochondria dynamically regulate their organization via opposing fusion and fission pathways to maintain bioenergetic homeostasis and contribute to key cellular pathways. This dynamic balance is directly linked to bioenergetic function: loss of transmembrane potential across the inner membrane (Dwm) disrupts mitochondrial fission/fusion balance, causing fragmentation of the network. However, the level of Dwm required for mitochondrial dynamic balance, as well as the relative contributions of fission and fusion pathways, have remained unclear. To explore this, mitochondrial morphology and Dwm were examined via confocal imaging and tetramethyl rhodamine ester (TMRE) flow cytometry, respectively, in cultured 143B osteosarcoma cells. When normalized to the TMRE value of untreated 143B cells as 100%, both genetic (mtDNA-depleted q0) and pharmacological [carbonyl cyanide m-chlorophenyl hydrazone (CCCP)-treated] cell models below 34% TMRE fluorescence were unable to maintain

mitochondrial interconnection, correlating with loss of fusion-active long OPA1 isoforms (L-OPA1). Mechanistically, this threshold is maintained by mechanistic coordination of DRP1-mediated fission and OPA1-mediated fusion: cells lacking either DRP1 or the OMA1 metalloprotease were insensitive to loss of Dwm, instead maintaining an obligately fused morphology. Collectively, these findings demonstrate a mitochondrial ‘tipping point’ threshold mediated by the interaction of Dwm with both DRP1 and OMA1; moreover, DRP1 appears to be required for effective OPA1 maintenance and processing, consistent with growing evidence for direct interaction of fission and fusion pathways. These results suggest that Dwm below threshold coordinately activates both DRP1-mediated fission and OMA1 cleavage of OPA1, collapsing mitochondrial dynamic balance, with major implications for a range of signaling pathways and cellular life/death events.

Comments

© The Author(s) 2016. Original published version available at http://dx.doi.org/10.1007/s00018-016-2421-9

Recommended Citation

Jones, E., Gaytan, N., Garcia, I. et al. A threshold of transmembrane potential is required for mitochondrial dynamic balance mediated by DRP1 and OMA1. Cell. Mol. Life Sci. 74, 1347–1363 (2017). https://doi.org/10.1007/s00018-016-2421-9

First Page

1347

Last Page

1363

Publication Title

Cellular and Molecular Life Sciences

DOI

10.1007/s00018-016-2421-9