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Coupled regulations of enzymatic activity and structure formation of aldehyde dehydrogenase Ald4p.

ABSTRACT: Previously, we have developed an extramitochondrial assembly system, where mitochondrial targeting signal (MTS) can be removed from a given mitochondrial enzyme, which could be used to characterize the regulatory factors involved in enzyme assembly/disassembly in vivo Here, we demonstrate that addition of exogenous acetaldehyde can quickly induce the supramolecular assembly of MTS-deleted aldehyde dehydrogenase Ald4p in yeast cytoplasm. Also, by using PCR-based modification of the yeast genome, cytoplasmically targeted Ald4p cannot polymerize into long filaments when key functional amino acid residues are substituted, as shown by N192D, S269A, E290K and C324A mutations. This study has confirmed that extramitochondrial assembly could be a powerful external system for studying mitochondrial enzyme assembly, and its regulatory factors outside the mitochondria. In addition, we propose that mitochondrial enzyme assembly/disassembly is coupled to the regulation of a given mitochondrial enzyme activity.

SUBMITTER: Noree C

PROVIDER: S-EPMC7197708 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Coupled regulations of enzymatic activity and structure formation of aldehyde dehydrogenase Ald4p.

Noree Chalongrat C Sirinonthanawech Naraporn N

Biology open 20200428 4

Previously, we have developed an extramitochondrial assembly system, where mitochondrial targeting signal (MTS) can be removed from a given mitochondrial enzyme, which could be used to characterize the regulatory factors involved in enzyme assembly/disassembly <i>in vivo</i> Here, we demonstrate that addition of exogenous acetaldehyde can quickly induce the supramolecular assembly of MTS-deleted aldehyde dehydrogenase Ald4p in yeast cytoplasm. Also, by using PCR-based modification of the yeast g ...[more]

PMID: 32295831

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Project description:BackgroundAldehyde dehydrogenase (ALDH) is highly expressed in stem/progenitor cells in various tissues, and cell populations with high ALDH activity (ALDHbr) are associated with tissue repair. However, little is known about lung-resident ALDHbr. This study was performed to clarify the characteristics of lung-resident ALDHbr cells and to evaluate their possible use as a tool for cell therapy using a mouse model of bleomycin-induced pulmonary fibrosis.MethodsThe characteristics of lung-resident/nonhematopoietic (CD45-) ALDHbr cells were assessed in control C57BL/6 mice. The kinetics and the potential usage of CD45-/ALDHbr for cell therapy were investigated in bleomycin-induced pulmonary fibrosis. Localization of transferred CD45-/ALDHbr cells was determined using mCherry-expressing mice as donors. The effects of aging on ALDH expression were also assessed using aged mice.ResultsLung CD45-/ALDHbr showed higher proliferative and colony-forming potential than cell populations with low ALDH activity. The CD45-/ALDHbr cell population, and especially its CD45-/ALDHbr/PDGFRα+ subpopulation, was significantly reduced in the lung during bleomycin-induced pulmonary fibrosis. Furthermore, mRNA expression of ALDH isoforms was significantly reduced in the fibrotic lung. When transferred in vivo into bleomycin-pretreated mice, CD45-/ALDHbr cells reached the site of injury, ameliorated pulmonary fibrosis, recovered the reduced expression of ALDH mRNA, and prolonged survival, which was associated with the upregulation of the retinol-metabolizing pathway and the suppression of profibrotic cytokines. The reduction in CD45-/ALDHbr/PDGFRα+ population was more remarkable in aged mice than in young mice.ConclusionsOur results strongly suggest that the lung expression of ALDH and lung-resident CD45-/ALDHbr cells are involved in pulmonary fibrosis. The current study signified the possibility that CD45-/ALDHbr cells could find application as novel and useful cell therapy tools in pulmonary fibrosis treatment.

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Coupled regulations of enzymatic activity and structure formation of aldehyde dehydrogenase Ald4p.

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Coupled regulations of enzymatic activity and structure formation of aldehyde dehydrogenase Ald4p.

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