Telomeric injury by KML001 in human T cells induces mitochondrial dysfunction through the p53-PGC-1α pathway

Area of Science:

• Immunology
• Cellular Biology
• Aging Research

Background:

• Telomere erosion and mitochondrial dysfunction are hallmarks of cellular aging.
• The impact of telomere injury on T lymphocyte mitochondrial function is not well understood.
• Previous work showed KML001 induces T cell senescence via telomeric DNA damage response (DDR).

Purpose of the Study:

• To investigate the role and mechanism of telomere injury in mitochondrial dysregulation in aging T cells.
• To determine if telomere damage directly induces mitochondrial dysfunction in human T lymphocytes.
• To elucidate the molecular pathways linking telomere integrity to mitochondrial health in T cells.

Main Methods:

• Utilized KML001, a telomere-targeting drug, to induce telomere damage in human T lymphocytes.
• Assessed mitochondrial function through measurements of swelling, membrane potential, oxidative phosphorylation, DNA content, respiration, glycolysis, and ATP production.
• Investigated molecular mechanisms involving the telomeric DNA damage response (DDR), p53 signaling, PGC-1α, and NRF-1 expression.

Main Results:

• KML001-induced telomere targeting led to significant mitochondrial dysfunction, including swelling and reduced membrane potential.
• Key mitochondrial functions such as oxidative phosphorylation, respiration, glycolysis, and ATP production were decreased.
• Mechanistically, telomeric DDR activated p53, which suppressed PGC-1α and NRF-1, causing mitochondrial dysfunction.

Conclusions:

• Telomere injury directly induces mitochondrial dysfunction in human T lymphocytes.
• The p53-PGC-1α-NRF-1 axis is a critical mediator of mitochondrial dysfunction in response to telomeric DDR.
• Targeting this axis presents a novel therapeutic strategy for immune aging and associated diseases.