Living longer through mitochondrial housekeeping

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Lithocholic bile acid accumulated in yeast mitochondria orchestrates a development of an anti-aging cellular pattern by causing age-related changes in cellular proteome

Mitochondria have long been known to be the powerhouse of the eukaryotic cell. This is the organelle where the bulk of ATP is generated through the electron transport chain, biosynthetic byproducts are synthesized, and free radicals are produced.^1,2 As such, mitochondria are critical for many cellular processes including cell growth, metabolic regulation, aging, disease, and apoptosis. The free radical theory of aging postulates that free radicals produced by the mitochondria are critical players in the aging process. Whether or not this is the whole story is up for debate, but mitochondrial function is still at the heart of the aging debate.³

A recent article in Cell Cycle by Dr. Titorenko's group sheds light on the role mitochondria play in normal yeast aging. Recent work from his laboratory shows that the bile acid, lithocholic acid (LCA), has the ability to increase the chronological lifespan of calorically restricted yeast cells, and accumulates in mitochondrial membranes, thereby altering the mitochondrial lipidome.^4,5 In their present report,⁶ mass spectrometry was utilized to scrutinize the protein changes that occur within mitochondria and the whole cell following exposure to LCA. Cells growing in low glucose concentrations were supplemented with LCA, or left untreated, with cells harvested after 2, 5 and 9 days to represent diauxic (D) growth, post-diauxic (PD) growth and stationary (ST) phase. It was observed that LCA altered the expression of proteins involved in multiple age-related processes, including those involved in the TCA cycle, the ETC, amino acid biosynthesis, heme synthesis and attachment, ROS detoxification, mitochondrial stress response, mitochondrial RNA synthesis and processing, as well as mitochondrial protein import and fission/fusion. A bioinformatics analysis of the protein changes revealed that the proteins could be grouped into 2 regulons defined by different mitochondrial dysfunctions, termed partial mitochondrial dysfunction (PMD) and oxidative stress (OS). Each regulon was further grouped into clusters, where expression of individual factors was limited to either the D, PD or ST phases of growth. Interestingly, regardless of whether expression was in D, PD or ST, the PMD regulon was controlled by the transcription factors Rtg1/Rtg2/Rtg3, Sfp1 and Aft1, whereas the OS regulon depended on the transcription factors Yap1, Msn2/Msn4, Skn1 and Hog1. Moreover, suspecting that the observed age-dependent mitochondrial protein changes that occurred upon LCA exposure may influence whole cell functions, proteins from the whole yeast cell were extracted and compared by mass spectrometry following exposure to LCA and grown to the D, PD and ST phases of the life cycle. Whole cell metabolic activities influenced by mitochondrial function, such as glycogen degradation, the glycolytic and pentose phosphate pathways, conversion of pyruvate to acetyl-CoA, maintenance of the NAD/NADH redox balance, ROS detoxification, gluconeogenesis, ethanol formation, and several others, were all altered by exposure to LCA. The PMD and OD regulons also defined these whole cell proteins and the transcription factors found to control the mitochondrial PMD and OS regulons also controlled the whole cell PMD and OS regulons. Thus, it is clear that LCA induces whole cell protein alterations in an age-dependent manner that control a host of mitochondrial events that ultimately increase the response of the cell to multiple stresses that occur as a cell ages.

Consistent with the notion that the transcription factors identified as controlling the expression of the PMD and OS regulons play a role in coordinating the time- and age-dependent expression of a suite of mitochondrial proteins in response to LCA exposure, deletion of any one of the identified transcription factors dramatically reduced the ability of LCA to induce extended lifespan under calorically restricted conditions. The observation that deletion of a single transcription factor could impair the ability of the cell to respond to LCA indicates that the yeast cell mounts a coordinated and complex response to age-dependent stresses, mediated via the mitochondria, that must act in a unified manner to fully benefit from calorically restricted conditions. While the work presented by Titorenko's group does not put to rest the debate on the free radical theory of aging, it certainly provides a plethora of evidence supporting the mitochondria's role in promoting health aging.