Peroxisomes are highly metabolic, autonomously replicating organelles that generate ROS as a by product of fatty acid β-oxidation. Consequently, cells must maintain peroxisome homeostasis, or risk pathologies associated with too few peroxisomes, such as peroxisome biogenesis disorders, or too many peroxisomes, inducing oxidative damage and promoting diseases such as cancer. We report that the PEX5 peroxisome import receptor binds ataxia-telangiectasia mutated (ATM) and localizes this kinase to the peroxisome. In response to reactive oxygen species (ROS), ATM signaling activates ULK1 and inhibits mTORC1 to induce autophagy. Specificity for autophagy of peroxisomes (pexophagy) is provided by ATM phosphorylation of PEX5 at Ser141, which promotes PEX5 mono-ubiquitination at K209, and recognition of ubiquitinated PEX5 by the autophagy adapter protein p62, directing the autophagosome to peroxisomes to induce pexophagy. These data reveal an important new role for ATM in metabolism as a sensor of ROS that regulates pexophagy.

Ataxia-telangiectasia mutated (ATM) plays a central role in DNA damage responses, and its loss leads to development of T-cell malignancies. Here, we show that ATM loss also leads to intrinsic mitochondrial abnormalities in thymocytes, including elevated reactive oxygen species, increased aberrant mitochondria, high cellular respiratory capacity, and decreased mitophagy. A fraction of ATM protein is localized in mitochondria, and it is rapidly activated by mitochondrial dysfunction. Unexpectedly, allelic loss of the autophagy regulator Beclin-1 significantly delayed tumor development in ATM-null mice. This effect was not associated with rescue of DNA damage signaling but rather with a significant reversal of the mitochondrial abnormalities. These data support a model in which ATM plays direct roles in modulating mitochondrial homeostasis and suggest that mitochondrial dysfunction and associated increases in mitochondrial reactive oxygen species contribute to the cancer-prone phenotype observed in organisms lacking ATM. Thus, ataxia-telangiectasia should be considered, at least in part, as a mitochondrial disease.

Subcellular localization is emerging as an important mechanism for mTORC1 regulation. We report that the tuberous sclerosis complex (TSC) signaling node, TSC1, TSC2 and Rheb, localizes to peroxisomes, where it regulates mTORC1 in response to reactive oxygen species (ROS). TSC1 and TSC2 were bound by PEX19 and PEX5, respectively, and peroxisome-localized TSC functioned as a Rheb GAP to suppress mTORC1 and induce autophagy. Naturally occurring pathogenic mutations in TSC2 decreased PEX5 binding, abrogated peroxisome localization, Rheb GAP activity, and suppression of mTORC1 by ROS. Cells lacking peroxisomes were deficient in mTORC1 repression by ROS and peroxisome-localization deficient TSC2 mutants caused polarity defects and formation of multiple axons in neurons. These data identify a role for TSC in Users may view, print, copy, download and text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms COMPETING FINANCIAL INTERESTSThe authors declare that they have no competing financial interests. HHS Public Access Author Manuscript Author ManuscriptAuthor ManuscriptAuthor Manuscript responding to ROS at the peroxisome, and identify the peroxisome as a signaling organelle involved in regulation of mTORC1.Tuberous sclerosis complex (TSC) is a hereditary hamartoma syndrome caused by defects in either the TSC1 or TSC2 genes 1, 2 . The TSC tumor suppressor is a heterodimer comprised of tuberin (TSC2), a GTPase activating protein (GAP), and its activation partner hamartin (TSC1), which localizes the TSC tumor suppressor to endomembranes and protects TSC2 from proteasomal degradation 3,4 . TSC inhibits the activity of the small GTPase Rheb to repress mammalian target of rapamycin complex 1 (mTORC1) signaling, a negative regulator of autophagy [5][6][7][8][9][10][11][12] . mTORC1 is regulated by a variety of cellular stimuli including amino acids, mitogens such as insulin, glucose, and energy stress [13][14][15] . In the case of amino acids, which do not signal through TSC-Rheb pathway 15 , mTORC1 activity is regulated by the Rag GTPases, which form the Ragulator complex that localizes mTORC1 to the late endosome or lysosome compartment of cells [13][14][15][16][17][18] . We recently reported that TSC functions in a signaling node downstream of ataxia telangiectasia mutated (ATM) to repress mTORC1 in response to reactive oxygen species (ROS) 19 . However, identification of the specific subcellular compartment(s) in which the TSC tumor suppressor functions to regulate mTORC1 in response to ROS has heretofore remained elusive.Peroxisomes, carry out key metabolic functions in the cell including β-oxidation of fatty acids, and are a major source of cellular ROS 20,21 . Like mitochondria, peroxisomes are autonomously replicating organelles. Peroxisome biogenesis requires peroxin (PEX) proteins, which are essential for assembly of functional peroxisomes 22 . Specific PEX pro...

Pancreatic ductal adenocarcinoma (PDAC) develops a pronounced stromal response reflecting an aberrant wound-healing process. This stromal reaction features trans-differentiation of tissue-resident pancreatic stellate cells (PSCs) into activated cancer-associated fibroblasts (CAFs), a process induced by PDAC cells but of unclear significance for PDAC progression. Here we show that PSCs undergo a dramatic lipid metabolic shift during differentiation in the context of pancreatic tumorigenesis, including remodeling of the intracellular lipidome and secretion of abundant lipids in the activated, fibroblastic state. Specifically, stroma-derived lysophosphatidylcholines support PDAC cell synthesis of phosphatidylcholines, key components of cell membranes, and also facilitate production of the potent wound-healing mediator lysophosphatidic acid (LPA) by the extracellular enzyme autotaxin, which is overexpressed in PDAC. The autotaxin-LPA axis promotes PDAC cell proliferation, migration and AKT activation, and genetic or pharmacologic autotaxin inhibition suppresses PDAC growth in vivo. Our work demonstrates how PDAC cells exploit the local production of wound healing mediators to stimulate their own growth and migration.