Mitochondrial biogenesis: CO and NO too

Abstract

The cell’s mitochondrial mass and respiratory capacity are protected by a number of structurally distinct events within the cell, including changes in cytoskeletal morphology, the mitochondrial fusion and fission cycle, mitophagy, and mitochondrial biogenesis. These events safeguard mitochondrial function at times of increased cell stress by protecting existing mitochondria, by disposing of damaged organelles, and by replacing them with new ones. This process of mitochondrial quality control involves intricate nuclear and bi-genomic programs over which the endogenous gaseous mediators, nitric oxide (NO) and carbon monoxide (CO), exert substantial regulatory control. This talk addresses novel molecular mechanisms by which NO and CO stimulate the nuclear transcriptional regulators, including energy-sensing and redox-regulated transcription factors and co-activators involved in the induction of mitochondrial biogenesis. These mechanisms include the regulation of NO and CO production by the NO synthases and heme oxygenase-1 (HO-1), biochemical interactions of NO and CO with a limited number of specific mitochondrial proteins, and activation of unique, hierarchical, and overlapping signal transduction pathways that participate in the nuclear-encoded gene expression required for the synthesis of mitochondrial proteins, their importation into mitochondria, transcription and replication of mitochondrial DNA, and mitochondrial proliferation. The production of one or both gases effects tailored adjustments in mitochondrial mass, number, distribution, and/or phenotype in response to increasing requirements for cellular work, cell repair, and proliferation, particularly in response to inflammation and oxidative stress in the heart, liver, kidney, and other major organs. Emphasis is given to the contribution of the innate immune system to oxidative/nitrosative cycles of mitochondrial damage to which the host cell, to protect its energy supply and survive, induces mitochondrial biogenesis under the control of NO and CO in concert with the expression of a complement of anti-oxidant and anti-inflammatory defense genes. This multifunctional network increases cellular resistance to metabolic failure and cell death and promotes immune tolerance while the inflammatory stress is brought under control.