LKB1-regulated adaptive mechanisms are essential for neuronal survival following mitochondrial dysfunction

Hum Mol Genet. 2013 Mar 1;22(5):952-62. doi: 10.1093/hmg/dds500. Epub 2012 Nov 27.


Mitochondrial dysfunction plays an important role in the etiology of neurodegenerative diseases. However, the progressive nature of neuronal loss in genetic models of mitochondrial dysfunction suggests the presence of compensatory mechanisms promoting neuronal survival under these conditions. Here, we identified the energy metabolism kinase LKB1 as a key regulator of the compensatory mechanisms activated in neurons, following mitochondrial dysfunction. To accomplish this, we have created an in vivo neurodegenerative model based on the deletion of the mitochondrial protein apoptosis-inducing factor (AIF) in postmitotic neurons. Loss of mitochondrial function caused by AIF deletion induced several adaptive mechanisms, including increased glycolysis and mitochondrial biogenesis. Importantly, the activation of these adaptive mechanisms was abrogated by the deletion of one allele of LKB1, resulting in impaired neuronal survival. Because loss of mitochondrial function is a central mechanism implicated in neurodegenerative diseases, modulation of LKB1-dependent pathways may represent an important strategy to preserve neuronal survival and function.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinases
  • Animals
  • Apoptosis
  • Apoptosis Inducing Factor / genetics
  • Apoptosis Inducing Factor / metabolism
  • Cell Survival
  • Energy Metabolism / genetics
  • Humans
  • Mice
  • Mitochondria / genetics*
  • Mitochondria / pathology
  • Mitochondrial Diseases / genetics
  • Mitochondrial Diseases / metabolism*
  • Mitochondrial Diseases / physiopathology
  • Neurodegenerative Diseases / genetics*
  • Neurodegenerative Diseases / metabolism
  • Neurodegenerative Diseases / pathology
  • Neurons / cytology
  • Neurons / metabolism
  • Protein Serine-Threonine Kinases* / genetics
  • Protein Serine-Threonine Kinases* / metabolism


  • Apoptosis Inducing Factor
  • Protein Serine-Threonine Kinases
  • Stk11 protein, mouse
  • AMP-Activated Protein Kinases