Induction of lysosomal and mitochondrial biogenesis by AMPK phosphorylation of FNIP1

Induction of lysosomal and mitochondrial biogenesis by AMPK phosphorylation of FNIP1. Malik, N., Ferreira, B. I., Hollstein, P. E., Curtis, S. D., Trefts, E., Novak, S. W., Yu, J., Gilson, R., Hellberg, K., Fang, L., Sheridan, A., Hah, N., Shadel, G. S., Manor, U., & Shaw, R. J. Science, 380(6642):eabj5559, 2023.

Paper doi abstract bibtex 1 download

Cells respond to mitochondrial poisons with rapid activation of the adenosine monophosphate–activated protein kinase (AMPK), causing acute metabolic changes through phosphorylation and prolonged adaptation of metabolism through transcriptional effects. Transcription factor EB (TFEB) is a major effector of AMPK that increases expression of lysosome genes in response to energetic stress, but how AMPK activates TFEB remains unresolved. We demonstrate that AMPK directly phosphorylates five conserved serine residues in folliculin-interacting protein 1 (FNIP1), suppressing the function of the folliculin (FLCN)–FNIP1 complex. FNIP1 phosphorylation is required for AMPK to induce nuclear translocation of TFEB and TFEB-dependent increases of peroxisome proliferator–activated receptor gamma coactivator 1-alpha (PGC1α) and estrogen-related receptor alpha (ERRα) messenger RNAs. Thus, mitochondrial damage triggers AMPK-FNIP1–dependent nuclear translocation of TFEB, inducing sequential waves of lysosomal and mitochondrial biogenesis. The kinase AMPK is a key sensor that helps to control energy homeostasis. Malik et al. reveal the mechanism by which AMPK controls the transcription factor TFEB to increase gene transcription and to support mitochondrial and lysosomal biogenesis. AMPK appears to act by direct phosphorylation of folliculin-interacting protein 1 (FNIP1). FNIP is part of a complex that acts as a GTP-activating protein for the GTPases RagC and RagD, which regulate the mechanistic target of rapamycin complex 1 protein kinase signaling complex on the lysosomal surface. This results in release of TFEB from the lysosome, allowing it to act at the nucleus. —LBR The energy-sensing protein kinase AMPK also regulates organelle biogenesis.

@article{doi:10.1126/science.abj5559,
  author = {Nazma Malik  and Bibiana I. Ferreira  and Pablo E. Hollstein  and Stephanie D. Curtis  and Elijah Trefts  and Sammy Weiser Novak  and Jingting Yu  and Rebecca Gilson  and Kristina Hellberg  and Lingjing Fang  and Arlo Sheridan  and Nasun Hah  and Gerald S. Shadel  and Uri Manor  and Reuben J. Shaw },
  title = {Induction of lysosomal and mitochondrial biogenesis by AMPK phosphorylation of FNIP1},
  journal = {Science},
  volume = {380},
  number = {6642},
  pages = {eabj5559},
  year = {2023},
  doi = {10.1126/science.abj5559},
  URL = {https://www.science.org/doi/abs/10.1126/science.abj5559},
  eprint = {https://www.science.org/doi/pdf/10.1126/science.abj5559},
  abstract = {Cells respond to mitochondrial poisons with rapid activation of the adenosine monophosphate–activated protein kinase (AMPK), causing acute metabolic changes through phosphorylation and prolonged adaptation of metabolism through transcriptional effects. Transcription factor EB (TFEB) is a major effector of AMPK that increases expression of lysosome genes in response to energetic stress, but how AMPK activates TFEB remains unresolved. We demonstrate that AMPK directly phosphorylates five conserved serine residues in folliculin-interacting protein 1 (FNIP1), suppressing the function of the folliculin (FLCN)–FNIP1 complex. FNIP1 phosphorylation is required for AMPK to induce nuclear translocation of TFEB and TFEB-dependent increases of peroxisome proliferator–activated receptor gamma coactivator 1-alpha (PGC1α) and estrogen-related receptor alpha (ERRα) messenger RNAs. Thus, mitochondrial damage triggers AMPK-FNIP1–dependent nuclear translocation of TFEB, inducing sequential waves of lysosomal and mitochondrial biogenesis. The kinase AMPK is a key sensor that helps to control energy homeostasis. Malik et al. reveal the mechanism by which AMPK controls the transcription factor TFEB to increase gene transcription and to support mitochondrial and lysosomal biogenesis. AMPK appears to act by direct phosphorylation of folliculin-interacting protein 1 (FNIP1). FNIP is part of a complex that acts as a GTP-activating protein for the GTPases RagC and RagD, which regulate the mechanistic target of rapamycin complex 1 protein kinase signaling complex on the lysosomal surface. This results in release of TFEB from the lysosome, allowing it to act at the nucleus. —LBR The energy-sensing protein kinase AMPK also regulates organelle biogenesis.}
  }

Downloads: 1