Mitochondria: Life, Death and the Agents of Aging

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Mitochondria in Mammalian Lung Tissue. Image by Louisa Howard

Despite propaganda to the contrary, aging is rarely a pleasurable experience.  A lifetime of damage to cells and tissues results in malfunction, making old age a significant risk factor for ailments such as cancers and neurologic disabilities typified by Alzheimer’s disease.  As a consequence, the graying of world populations has triggered a scientific frenzy to unravel the basic processes behind aging and find ways to slow down and perhaps even prevent age-related degeneration.

“Two linked ideas are at the core of our current aging theory,” says molecular cell biologist Colin Dingwall at Kings College, London “The first is that proteins, RNA and DNA are bombarded with and damaged by reactive oxygen species (ROS) generated during normal cellular respiration and this results in eventual decline and disease.  The second is that mitochondria are the major culprits behind aging.” This is to be expected, these tiny bacterial endosymbionts produce most of a eukaryotic cell’s energy and ROS generation is an inevitable byproduct of the process.

“Moreover,” according to Dingwall, “micro-injection of mitochondria from ‘young’ cells, those which haven’t divided very much, can overcome senescence in cells that are reaching the natural end of their lives and will probably, in the usual course of things, undergo programmed cell death, or apoptosis which is also largely controlled by mitochondria.” Further support for the ‘mitochondrial theory’ of aging, he adds, comes from studies in a range of organisms including yeast, nematode worms, flies and mice showing that by silencing certain mitochondrial genes –mitochondria have their own circular genomes—life span is extended.

Not all mitochondrial-induced aging is caused by ROS – at least not in mice

A series of studies in mice has yielded an unexpected result, continues Dingwall. “While defects in mitochondrial function did give rise to an aging phenotype, this was not accompanied by any detectable changes in ROS generation, he explains.

Like all bacteria, mitochondria strive to be small, fast and flexible.  Thus the mitochondrial genome encodes only 13 respiratory chain polypeptides -all the other protein-coding genes have been jetted into the host’s linear genome and protein manufacture outsourced to the host. Among the few proteins mitochondria consider important enough to encode themselves is an enzyme called DNA polymerase gamma, without which, mitochondrial DNA cannot replicate.

Mutant mice look old and die young, but ROS levels normal

Transgenic mice, mutants in which DNA polymerase gamma has been rendered ‘error prone,’ show an age-dependent linear increase in mitochondrial DNA damage and hence the proteins encoded by this defective DNA are also defected. The mice look old, continues Dingwall, they lose weight, their subcutaneous fat is reduced, they lose hair, their bone density is reduced and they develop curvature of the spine. These mice also don’t live as long as normal ones; whereas more than 90% of the non-mutant control mice were happily hopping about their cages at 61 weeks, all of the mutant mice had already died of age-related causes.

Despite these clear phenotypic changes, there were no detectable changes in ROS production in mutant mouse tissue and no change in the levels of ROS-induced damage to proteins. Equally, there was also no increase in the levels of anti-oxidant defense enzymes. In other words, the mutant mice look old and die young but ROS levels and protein damage normal.

If increased ROS is not responsible for aging in these mice,” asks Dingwall, “what is?”  He believes that alteration of mitochondrial function in certain key tissues triggers a response in distant tissue. Mitochondria have evolved from an endosymbiont alpha-proteobacterium -a relative of Brucella and rickettsia- and are quintessentially bacterial. Bacteria chatter incessantly; perhaps our mitochondria communicate via a network of cell signaling, running the show from a distance.  In this way, localized change could determine the rate of aging for the whole organism and this could be independent of damage caused by ROS. Experiments that test this idea are planned. 

ROS isn’t always bad and antioxidants aren’t always good

Not all cancers are promoted by reactive oxygen species; some have adaptive mechanisms to keep their ROS burden within manageable levels and “enhanced ROS detoxification…may in fact be pro-tumorigenic,” according to a recent study by David A. Tuveson and colleaguesat the Cambridge Research Institute in the U.K. These new data, say Rushika M. Perera and Nabeel Bardeesy from Harvard Medical School’s Cancer Center in Boston, Massachusetts calls for “a more nuanced view of the impact of ROS” on cancer development.

Does this imply that dietary antioxidants will increase the risk of some cancers? “Probably not,” answer Perera and Bardeesy, because antioxidant supplementation only had a positive effect on tumor formation when a particular mouse antioxidant program, Nrf2, was knocked out, “a context unlikely to be seen in human tumorigenesis.” But they add that “These observations highlight the context-dependent roles of ROS in cancer.”

Furthermore, macrophages need ROS to kill intracellular bacteria and they recruit mitochondria to help in the fight. A new study led by Sankar Ghosh at Columbia University in New York City  reveals “a novel pathway linking innate immune signaling to mitochondria, implicate  mitochondrial ROS as an important component of antibacterial responses…and further establish mitochondria as hubs for innate immune signaling.”  Yet another example of the positive effects of ROS.

Sources:

Brenner, Catherine and Kroemer, Guido: Mitochondria –the Death Signal Integrators. In Science (2000); 289, pp. 1150-1151.

DeNicola, Gina M et al: Oncogene-induced Nrf2 transcription promotes ROS detoxification and tumorigensis. In Nature (2011); 475, pp 106-109.

Manfredi, Angelo A and Rovere-Querini, Patrizia: The Mitochondrion –A Trojan Horse That Kicks Off Inflammation? In N Engl J. Med (2010); 362, pp. 2132-2134.

Perera, Rushika M. and Bardeesy, Nabeel: When antioxidants are bad. In Nature (2011); 475, pp 4344.

West, AP, et al: TLR signaling augments macrophage bacterial activity through mitochondrial ROS in Nature (2011); 473, pp. 476-480.

West, A. Phillip et al: TLR signaling augments macrophage bactericidal activity through mitochondrial ROS. In Nature (2011); 472, pp. 476-480.

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