Rv0547c, a functional oxidoreductase, supports Mycobacterium tuberculosis persistence by reprogramming host...

Area of Science:

• Microbiology
• Cell Biology
• Biochemistry

Background:

• Mycobacterium tuberculosis (Mtb) employs metabolic adaptation and host manipulation for survival.
• Understanding Mtb's persistence mechanisms is crucial for developing effective treatments.

Purpose of the Study:

• To investigate the role of Rv0547c, a protein with a predicted mitochondria-targeting sequence (MTS), in Mtb persistence.
• To elucidate how Rv0547c affects host cell mitochondria and bacterial survival.

Main Methods:

• Investigated Rv0547c localization and function in host-cell mitochondria.
• Performed comparative lipidomics and analyzed mitochondrial fractions.
• Assessed oxygen consumption rate (OCR) in HEK293T cells.
• Evaluated Mtb persistence in THP-1 macrophages.

Main Results:

• Rv0547c targets host mitochondria independently of its predicted MTS, dependent on specific arginine residues.
• Rv0547c enhances mitochondrial membrane fluidity and spare respiratory capacity.
• Altered fatty acid metabolism, including propionate and beta-oxidation pathways, was observed.
• Rv0547c expression increased Mtb persistence in macrophages and M. smegmatis survival under stress.

Conclusions:

• Rv0547c is the first identified Mtb protein that modulates host mitochondrial metabolism, specifically fatty acid oxidation.
• This modulation enhances bacterial survival in host macrophages by increasing mitochondrial spare respiratory capacity and mitigating stress.
• Rv0547c plays a significant role in Mtb persistence and viability.