Tailoring mitochondria to the cell's needs

Cells increase their complement of mitochondria in response to rising metabolic demands or altered physiological conditions. This biosynthetic process is complicated, in part because mitochondrial composition varies between cell types. All cells depend on mitochondrial oxidative phosphorylation (OxPhos), but some--notably adult cardiac myocytes-- are specialized for metabolizing fatty acids in their mitochondria. Most other cells, including those in the neonatal heart, rely on the reducing power generated as glucose is metabolized in the cytoplasm. Likewise, mitochondria in brown adipose tissue (BAT), but not in most other cells, contain high levels of uncoupling proteins that allow OxPhos to generate heat rather than ATP.

Lehman et al. now show that the transcriptional co-activator PGC-1 is limiting for mitochondrial proliferation in cardiac muscle, and they argue that this factor helps direct quantitative and qualitative changes in the mitochondrial population of various cells. PGC-1 interacts with PPARa in heart cells (and with PPARg or other transcription factors elsewhere) to activate mitochondrial biogenesis. PGC-1 and PPARg mediate BAT's response to cold, but in cardiac myocytes, as Lehman and colleagues now show, PGC-1 and PPARa activate mitochondrial proliferation during fasting and at other times when fatty acid oxidation becomes increasingly important to meet the heart's energy needs. Overexpressing PGC-1in cardiac cells increases cells' capacity to carry out fatty acid oxidation and coupled OxPhos. Because this transgene activates a different set of genes and functions in BAT, the authors suggest that pairing of PGC-1with PPARa specifies the expression of cardiac mitochondrial components. The importance of maintaining tight control over this regulatory system is seen in the phenotype of transgenic mice expressing PGC-1 constitutively in the heart. These animals show a dramatic proliferation of cardiac mitochondria but develop dilated cardiomyopathy and die at an early age. How increased mitochondrial function might alter heart development is still unknown.