Mitochondrial biogenesis: Which part of “NO” do we understand?

Abstract

SummaryA recent paper by Nisoli et al. (1) provides the first evidence that elevated levels of nitric oxide (NO) stimulate mitochondrial biogenesis in a number of cell lines via a soluble guanylate-cyclase-dependent signaling pathway that activates PGC1a (peroxisome proliferator-activated receptor g coactivator-1a), a master regulator of mitochondrial content. These results raise intriguing possibilities for a role of NO in modulating mitochondrial content in response to physiological stimuli such as exercise or cold exposure. However, whether this signaling cascade represents a widespread mechanism by which mammalian tissues regulate mitochondrial content, and how it might integrate with other pathways that control PGC1a expression,remainunclear. BioEssays25:538-541,2003. ß 2003 Wiley Periodicals, Inc. IntroductionMitochondria produce the bulk of the ATP required for the normal function of most tissues. As such, the mitochondrial content of a given tissue largely reflects its specific demands for respiratory energy. In specialized tissues such as brown fat, which has a thermogenic role in neonates and hibernating animals, mitochondria express an uncoupling protein (UCP1) that functionally dissociates electron transport from oxidative phosphorylation, allowing the energy released in this process to be dissipated as heat. (2) Increased physiological demand for aerobic ATP production or the generation of heat results in mitochondrial proliferation. Several families of unrelated transcription factors, most notably the nuclear respiratory factors (NRFs), modulate the increased expression of nuclearencoded mitochondrial proteins necessary for increased biogenesis of the organelle. (3) The activity of many of these transcription factors is in turn controlled by the co-activator PGC1a, and its related family members. (4) PGC1a also potentiates the expression of a large number of additional genes via its interactions with members of the nuclear hormone receptor superfamily. (5)

ER stress response, peroxisome proliferation, mitochondrial unfolded protein response and Golgi stress response

“…It has been reported that the mass of mammalian mitochondria is increased in cells that have defects in the respiratory chain (74), adipose tissue upon cold shock (75) or exercise-conditioned skeletal muscle (1), suggesting that the mitochondria has an autoregulatory system to adjust its function for cellular demand, to keep ATP levels constant (76). Although transcription factors and coactivators such as Tfam, NRF1, NRF2, SP1, YY1, CREB, MEF2 and PGC-1 alpha are reported to be involved in the transcriptional induction of genes responsible for mitochondrial function and biogenesis, the mitochondrial biosynthetic program appears to be regulated by multiple transcriptional regulatory pathways, including the mitochondrial retrograde signaling and mitochondrial unfolded protein response.…”

Mitochondrial-Nuclear Communications

“…These conditions manifest themselves in pathologies associated with tissues strictly dependent on proper mitochondrial function, such as nerve and muscle tissues (1)(2)(3). There is a direct correlation between energy demand and mitochondrial abundance, pointing to sophisticated regulatory mechanisms that control mitochondrial biogenesis (4).…”

A common mitchondrial DNA variant is associated with thinness in mothers and their 20-yr-old offspring

“…Mitochondrial (mt) function is emerging as an important contributor to the risk of diabetes (19,23,25) and other diseases related to aging (24,35). Transcription factors regulating the formation and activity of fat cells (6) are also regulators of mitochondrial function (14). Drugs used for treating AIDS that result in mtDNA depletion (due to inhibition of the mtDNA DNA polymerase) affect adipocyte differentiation both in vivo (22) and in tissue culture.…”