Activation of the Hog1p kinase in Isc1p-deficient yeast cells is associated with mitochondrial dysfunction, oxidative stress sensitivity and premature aging

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

“…4,57 The OS regulon includes the following clusters: (1) a cluster governed by the transcription factor Yap1p, a primary determinant in the antioxidant response of yeast cells; [58][59][60][61][62][63][64] (2) a cluster governed by the transcription factors Msn2p/Msn4p, which are required for expression of numerous genes in response to thermal, oxidative and other types of stress; 56,62-65 (3) a cluster governed by the transcription factor Skn7p, which is involved in the osmotic and oxidative stress responses; [58][59][60][61][62][63][64] and (4) a cluster governed by Hog1p, a mitogen-activated protein kinase orchestrating an osmosensing signal transduction pathway in yeast. 64,66,67 It needs to be emphasized that mitochondrial proteins constituting the PMD and OS regulons exhibit 3 different patterns of the age-related dynamics of changes in their cellular levels; to underscore the existence of such differences in expression, we separated each of the PMD and OS regulons into regulons "type 1", "type 2" and "type 3" (Fig. 2 and Table S1).…”

“…4,56,57 The expression of genes coding for mitochondrial proteins that belong to the OS regulons type 1, 2 and 3 has been shown to be under the control of the transcription factors Yap1p, Msn2p/Msn4p, Skn7p and Hog1p. [58][59][60][61][62][63][65][66][67] LCA causes age-related changes in cellular proteome Age-related alterations in the rates and efficiencies of several processes within mitochondria are known to modulate the capacity of these organelles to make and release certain molecular signals; outside mitochondria, such signals have been shown to cause changes in the rates and efficiencies of longevity-defining processes in other cellular locations. [3][4][5][6]16,20,25,31,33,56 Of note, we found that a treatment of yeast cells with LCA alters the agerelated chronology of these mitochondrial processes.…”

“…4). 4,5,56,[58][59][60][61][62][63][65][66][67] We also found that, akin to mitochondrial proteins constituting the PMD and OS regulons, cellular proteins that belong to each of them displays either of the following 3 patterns of age-related changes in their levels: (1) the levels of cellular proteins that belong to the PMD and OS regulons type 1 remained nearly unchanged during D and PD growth phases but underwent a 3-4 fold rise or reduction during the subsequent ST growth phase ( Fig. 4; PMD regulon 1 and OS regulon 1); (2) the levels of cellular proteins that belong to the PMD and OS regulons type 2 increased by 3-4 folds during D and PD growth phases but remained almost unaltered during the following ST growth phase ( Fig.…”

“…Moreover, we noted that: (1) similar to mitochondrial proteins constituting the 3 different PMD regulons, the expression of genes for cellular proteins that belong to the PMD regulons type 1, 2 and 3 has been shown to be governed by the transcription factors Rtg1p/Rtg2p/Rtg3p, Sfp1p and Aft1p; 4,56,57 and (2) akin to mitochondrial proteins constituting the 3 different OS regulons, the expression of genes for cellular proteins that belong to the OS regulons type 1, 2 and 3 is known to be controlled by the transcription factors Yap1p, Msn2p/Msn4p, Skn7p and Hog1p. [58][59][60][61][62][63][65][66][67] Longevity extension by LCA requires a distinct set of transcription factors…”

“…5 and S1); all these factors are known to cause a development of an anti-aging cellular pattern by activating specific transcriptional programs in the nucleus. 4,5,[55][56][57][58][59][60][61][62][63][65][66][67] In contrast, a single-gene-deletion mutation eliminating the transcription factor Aft1p increased the longevity-extending efficiency of LCA (Figs. 5 and S1); this factor has been shown to respond to reduced levels of cellular ISC by eliciting a pro-aging transcriptional program in the nucleus.…”