A small natural molecule promotes mitochondrial fusion through inhibition of the deubiquitinase USP30

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.

Signalling mechanisms underlying doxorubicin and Nox2 NADPH oxidase‐induced cardiomyopathy: involvement of mitofusin‐2

“…Therefore, a pharmacological strategy involving Mfn2 that could potentially prevent degeneration of both adult cardiac cells and the resident stem cell pool seems an attractive idea. Such an approach may be enabled by the identification of a small natural molecule, 15‐oxospiramilactone, which, through inhibition of a mitochondria‐localized deubiquitinase, increases Mfn2 activity (Yue et al, 2014), although effects have yet to be demonstrated in relevant models that could indicate potential targeting of this mechanism for translation to the clinic.…”

Mitofusins: ubiquitylation promotes fusion

“…Inhibition and activation of mitochondrial fusion by ubiquitylation enable different morphologies of mitochondria ranging from a multitude of small organelles to a hyperconnected network (Figure 1) [5]. In a recent paper published in Cell Research, Yue et al [6] reveal that a similar process is present in mammalian cells. The authors report that the isopeptidase USP30 acts on ubiquitylated forms of Mfn1 and Mfn2 that stimulate mitochondrial fusion ( Figure 1, right panel).…”

“…The authors report that the isopeptidase USP30 acts on ubiquitylated forms of Mfn1 and Mfn2 that stimulate mitochondrial fusion ( Figure 1, right panel). This discovery identifies for the first time in mammals a positive role of ubiquitylation in the regulation of Mfn1 and Mfn2 fusion activity [6].…”

“…15-oxospiramilactone is a semi-synthetic diterpene alkaloid of 330 Da that can be chemically synthetized through an oxidation reaction from spiramines extracted from the roots of a Chinese herbal medicine Spiraea japonica (Rosaceae). Inhibition of USP30 increased ubiquitylation of Mfn1 and Mfn2 and led to an elongation of the mitochondrial network ( Figure 1, right panel) [6,7]. USP30 is a cysteine ubiquitin isopeptidase N-terminally anchored to the outer membrane of mitochondria, which was previously shown to regulate mitochondrial morphology dependent on Mfn1 and Mfn2 [7].…”

“…Moreover, Yue et al [6] identified the first small molecule inhibitor of mitochondrial fusion, 15-oxospiramilactone, which targets USP30 in both human and mouse cell lines. 15-oxospiramilactone is a semi-synthetic diterpene alkaloid of 330 Da that can be chemically synthetized through an oxidation reaction from spiramines extracted from the roots of a Chinese herbal medicine Spiraea japonica (Rosaceae).…”