Abstract
Mitochondrial fusion is a highly coordinated process that mixes and unifies the mitochondrial compartment for normal mitochondrial functions and mitochondrial DNA inheritance. Dysregulated mitochondrial fusion causes mitochondrial fragmentation, abnormal mitochondrial physiology and inheritance, and has been causally linked with a number of neuronal diseases. Here, we identified a diterpenoid derivative 15-oxospiramilactone (S3) that potently induced mitochondrial fusion to restore the mitochondrial network and oxidative respiration in cells that are deficient in either Mfn1 or Mfn2. A mitochondria-localized deubiquitinase USP30 is a target of S3. The inhibition of USP30 by S3 leads to an increase of non-degradative ubiquitination of Mfn1/2, which enhances Mfn1 and Mfn2 activity and promotes mitochondrial fusion. Thus, through the use of an inhibitor of USP30, our study uncovers an unconventional function of non-degradative ubiquitination of Mfns in promoting mitochondrial fusion.
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Acknowledgements
We thank David C Chan (California Institute of Technology, USA) for generously providing us with the Mfn1−/−, Mfn2−/− and OPA1−/− cells and Mfn Dko cells. We thank Mark Bartlam (Nankai University, China) and Aiming Zhou (Cleveland State University Cleveland, USA) for their help on the writing. Research in Chen's laboratory was supported by the Natural Science Foundation of China (NSFC; 91213304 and 81130045), the Ministry of Sciences and Technology (2011CB910903 and 2010CB912204) and the NSFC-joint foundation of Yunnan Province (U1032603).
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Supplementary information
Supplementary information, Figure S1
The effect of S3 on cell viability. (PDF 221 kb)
Supplementary information, Figure S2
Functional Mfn1 or Mfn2 is required for S3-induced mitochondrial fusion. (PDF 120 kb)
Supplementary information, Figure S3
Quantification of mtDNA in Mfn1−/− and Mfn2−/− MEFs after S3 treating. (PDF 78 kb)
Supplementary information, Figure S4
S3-induced mitochondrial elongation does not occur through inhibition of Drp1. (PDF 129 kb)
Supplementary information, Figure S5
Synthesis of Biotin-labeled S3. (PDF 50 kb)
Supplementary information, Figure S6
S3 inhibited Deubiquitinase activity of USP30. (PDF 102 kb)
Supplementary information, Figure S7
Knock down of USP30 resembles the effects of S3 on mitochondrial function. (PDF 130 kb)
Supplementary information, Figure S8
S3-induced mitochondrial fusion is not dependent on SLP2. (PDF 99 kb)
Supplementary information, Data S1
Materials and Mathods (PDF 32 kb)
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Yue, W., Chen, Z., Liu, H. et al. A small natural molecule promotes mitochondrial fusion through inhibition of the deubiquitinase USP30. Cell Res 24, 482–496 (2014). https://doi.org/10.1038/cr.2014.20
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DOI: https://doi.org/10.1038/cr.2014.20
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