Mitochondrial Fusion Is Essential for Steroid Biosynthesis

Abstract

Although the contribution of mitochondrial dynamics (a balance in fusion/fission events and changes in mitochondria subcellular distribution) to key biological process has been reported, the contribution of changes in mitochondrial fusion to achieve efficient steroid production has never been explored. The mitochondria are central during steroid synthesis and different enzymes are localized between the mitochondria and the endoplasmic reticulum to produce the final steroid hormone, thus suggesting that mitochondrial fusion might be relevant for this process. In the present study, we showed that the hormonal stimulation triggers mitochondrial fusion into tubular-shaped structures and we demonstrated that mitochondrial fusion does not only correlate-with but also is an essential step of steroid production, being both events depend on PKA activity. We also demonstrated that the hormone-stimulated relocalization of ERK1/2 in the mitochondrion, a critical step during steroidogenesis, depends on mitochondrial fusion. Additionally, we showed that the SHP2 phosphatase, which is required for full steroidogenesis, simultaneously modulates mitochondrial fusion and ERK1/2 localization in the mitochondrion. Strikingly, we found that mitofusin 2 (Mfn2) expression, a central protein for mitochondrial fusion, is upregulated immediately after hormone stimulation. Moreover, Mfn2 knockdown is sufficient to impair steroid biosynthesis. Together, our findings unveil an essential role for mitochondrial fusion during steroidogenesis. These discoveries highlight the importance of organelles’ reorganization in specialized cells, prompting the exploration of the impact that organelle dynamics has on biological processes that include, but are not limited to, steroid synthesis.

LEOPARD syndrome-associated SHP2 mutation confers leanness and protection from diet-induced obesity

“…In addition, we could determine that some markers of adipose tissue beiging were upregulated in adipose tissues from LS mice, notably in s.c. fat pads, suggesting that this adipose tissue has enhanced oxidative activity, which could contribute to enhanced energy expenditure. Interestingly, several studies have shown that SHP2 could regulate mitochondria activity, although the signaling pathways that link SHP2, and its LS-associated mutants, to the regulation of mitochondria function and energy homeostasis remain to be documented (37)(38)(39)(40)(41)(42).…”

The role of mitochondrial fusion and StAR phosphorylation in the regulation of StAR activity and steroidogenesis

“…Moreover, SHP2 is needed for the correct association of ERK with mitochondria, as an indirect way of controlling StAR phosphorylation by ERK activity (Duarte et al, 2012).…”

“…Mfn2 is promptly up-regulated after the steroidogenic stimuli, thus suggesting that mitochondrial dynamics might be central for steroidogenesis. Furthermore, blocking mitochondrial fusion by knocking down Mfn2 expression has a negative impact on steroid synthesis (Duarte et al, 2012). The changes observed in mitochondrial fusion might also be central for the formation of the mitochondrial multiprotein complex that delivers cholesterol to the P450scc system, as hormone-stimulated mitochondrial rearrangement is required for the re-localization of the ERK1/2 protein to mitochondria.…”

Mitotane alters mitochondrial respiratory chain activity by inducing cytochrome c oxidase defect in human adrenocortical cells

“…Of particular interest, mitotane exposure also triggered morphologic fragmentation of the mt network, which could be related to disequilibrium between mt fission and fusion . It is well established that the integrity of mt outer and inner membranes is required for respiratory chain activity (Liesa et al 2009) and presumably steroidogenesis (Duarte et al 2012). It is not known, however, whether mt fragmentation has a direct relationship with or a causal role in genotoxic stress and apoptosis.…”