The role of AMP-activated protein kinase in mitochondrial biogenesis

Abstract

While it has been known for more than 75 years that physical activity is associated with increased mitochondrial content in muscle, the molecular mechanism for this adaptive process has only recently been elucidated. This brief review examines existing studies that have identified AMPK-activated protein kinase (AMPK) and several other key regulators of mitochondrial biogenesis, including peroxisome proliferator-activated receptor-gamma coactivator-1alpha and -1beta, calcium/calmodulin-dependent protein kinase IV, and nitric oxide. In addition, the potential role of mitochondrial dysfunction in the pathogenesis of insulin resistance associated with ageing and type 2 diabetes mellitus is also discussed.

Figure 1. Critical factors involved in mitochondrial biogenesis

CaMKIV, AMPK, and NO cause an increase in PGC-1α gene transcription, which results in gene expression of the NRFs, to which PGC-1α also binds and activates, and finally, mtTFA expression and initiation of mitochondrial DNA replication. The NRFs also induce OXPHOS gene transcription, and the resulting nuclear-encoded proteins then travel to the mitochondria. Lastly, mtTFA is able to transcribe mitochondrial DNA, which leads to the production of mitochondrial-encoded proteins.

Figure 2. Effect of β-GPA treatment on mitochondrial content as assessed by electron microscopy

Transgenic mice expressing a dominant-negative mutant form of AMPK in skeletal muscle and wild-type mice were fed β-GPA for 8 weeks. Mitochondrial content was then assessed by electron microscopy of the epitrochlearis (EPI) muscle of wildtype (WT) mouse (saline treated) (A), WT mouse (GPA treated) (B), dominant-negative AMPK transgenic mouse (saline treated) (C), and dominant-negative AMPK transgenic mouse (GPA treated) (D). Arrows point to mitochondria. (Scale bar, 1 μm.) E, mitochondria density (% of total volume) in the extensor digitorum longus (EDL) (n = 10 in each group) and EPI muscles of each group of mice (n = 5 in each group). *P < 0.05 compared with other groups. From Zhong et al. (2002). ©2002 National Academy of Sciences, USA.

Figure 3. Mitochondrial density and gene expression data of young, lean and sedentary insulin-resistant offspring of parents with type 2 diabetes and control subjects

Mitochondrial density in control subjects (n = 6) and insulin-resistant offspring (n = 8), assessed by electron microscopy. #, muscle fibre; *, mitochondrion.