Article

Control of mitochondrial structure and function by the Yorkie/YAP oncogenic pathway.

Department of Molecular, Cell, and Developmental Biology.
Genes & development (Impact Factor: 12.64). 08/2012; 26(18):2027-37. DOI: 10.1101/gad.183061.111
Source: PubMed

ABSTRACT Mitochondrial structure and function are highly dynamic, but the potential roles for cell signaling pathways in influencing these properties are not fully understood. Reduced mitochondrial function has been shown to cause cell cycle arrest, and a direct role of signaling pathways in controlling mitochondrial function during development and disease is an active area of investigation. Here, we show that the conserved Yorkie/YAP signaling pathway implicated in the control of organ size also functions in the regulation of mitochondria in Drosophila as well as human cells. In Drosophila, activation of Yorkie causes direct transcriptional up-regulation of genes that regulate mitochondrial fusion, such as opa1-like (opa1) and mitochondria assembly regulatory factor (Marf), and results in fused mitochondria with dramatic reduction in reactive oxygen species (ROS) levels. When mitochondrial fusion is genetically attenuated, the Yorkie-induced cell proliferation and tissue overgrowth are significantly suppressed. The function of Yorkie is conserved across evolution, as activation of YAP2 in human cell lines causes increased mitochondrial fusion. Thus, mitochondrial fusion is an essential and direct target of the Yorkie/YAP pathway in the regulation of organ size control during development and could play a similar role in the genesis of cancer.

0 Followers
 · 
160 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Fat (Ft) cadherins are enormous cell adhesion molecules that function at the cell surface to regulate the tumor-suppressive Hippo signaling pathway and planar cell polarity (PCP) tissue organization. Mutations in Ft cadherins are found in a variety of tumors, and it is presumed that this is due to defects in either Hippo signaling or PCP. Here, we show Drosophila Ft functions in mitochondria to directly regulate mitochondrial electron transport chain integrity and promote oxidative phosphorylation. Proteolytic cleavage releases a soluble 68 kDa fragment (Ft(mito)) that is imported into mitochondria. Ft(mito) binds directly to NADH dehydrogenase ubiquinone flavoprotein 2 (Ndufv2), a core component of complex I, stabilizing the holoenzyme. Loss of Ft leads to loss of complex I activity, increases in reactive oxygen species, and a switch to aerobic glycolysis. Defects in mitochondrial activity in ft mutants are independent of Hippo and PCP signaling and are reminiscent of the Warburg effect.
    Cell 09/2014; 158(6):1293-308. DOI:10.1016/j.cell.2014.07.036 · 33.12 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: PTEN-induced kinase 1 (Pink1) and ubiquitin E3 ligase Parkin function in a linear pathway to maintain healthy mitochondria via regulating mitochondrial clearance and trafficking. Mutations in the two enzymes cause the familial form of Parkinson's disease (PD) in humans, as well as accumulation of defective mitochondria and cellular degeneration in flies. Here we show that loss of function of a scaffolding protein Mask, also known as ANKHD1 (Ankyrin repeats and KH domain containing protein 1) in humans, rescues the behavioral, anatomical and cellular defects caused by pink1 or parkin mutations in a cell-autonomous manner. Moreover, similar rescue can also be achieved if Mask knock-down is induced in parkin adult flies when the mitochondrial dystrophy is already manifested. We found that Mask genetically interacts with Parkin to modulate mitochondrial morphology and negatively regulates the recruitment of Parkin to mitochondria. We also provide evidence that loss of Mask activity promotes co-localization of the autophagosome marker with mitochondria in developing larval muscle, and that an intact autophagy pathway is required for the rescue of parkin mutant defects by mask loss of function. Together, our data strongly suggest that Mask/ANKHD1 activity can be inhibited in a tissue- and timely-controlled fashion to restore mitochondrial integrity under PD-linked pathological conditions. Published by Oxford University Press 2015. This work is written by (a) US Government employee(s) and is in the public domain in the US.
    Human Molecular Genetics 03/2015; 24(11). DOI:10.1093/hmg/ddv081 · 6.68 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Emerging evidence strongly suggests that stem cells and their differentiated progeny display distinct metabolic profiles, but how metabolic changes are coupled with organogenesis has remained unclear. Homem et al. (2014) now reveal a hormone-dependent pathway that couples metabolic changes with stem cell differentiation, thereby terminating neurogenesis in the Drosophila brain.
    Cell Stem Cell 09/2014; 15(3):262–264. DOI:10.1016/j.stem.2014.08.006 · 22.15 Impact Factor