Loss-of-function mitochondrial DNA polymerase gamma variants cause vascular smooth muscle cells to secrete a diffusible mitogenic factor DOI Creative Commons

Samantha Rothwell,

Irvin Ng,

Sophia Shalchy-Tabrizi

и другие.

Frontiers in Physiology, Год журнала: 2025, Номер 15

Опубликована: Фев. 17, 2025

Introduction Mitochondrial dysfunction promotes vascular aging and disease through diverse mechanisms beyond metabolic supply, including calcium radical signaling inflammation. DNA (mtDNA) replication by the POLG-encoded mitochondrial polymerase (POLG) is critical for health. Loss-of-function POLG variants are associated with a predisposition to hypertension. We hypothesized that impaired POLG, reduced mtDNA copy number or other mechanisms, would promote smooth muscle hypertrophy hyperplasia drives remodeling Methods characterized effect of over-expressing were previously observed in cohort hypertensive patients (p.Tyr955Cys, p.Arg964Cys, p.Asn1098Ile, p.Arg1138Cys) A7r5 cells. Results AlphaFold modeling holoenzyme complexed predicted changes catalytic site p.Tyr955Cys p.Asn1098Ile variants, while p.Arg964Cys p.Arg1138Cys showed minimal effects. The number, assessed immunofluorescence droplet digital PCR, up 27% order > relative wild-type-transfected cultures. Loss was cultures grown low serum glucose media, but cell density increased same rank both 10% 1% serum. constructs contained Myc epitope, counterstaining which transfected cells untransfected neighbors. Live-cell imaging membrane potential TMRM oxygen species production MitoSOX little variants. had on consumption, Seahorse assay. growth analyses again decreased p.Arg1138Cys, HeLa Conditioned media from doubling times naïve Pharmacologically, wedelolactone MitoTEMPOL, not indomethacin PD98059, suppressed mitogenic effects Discussion conclude induces secretion signal even when below limit detection. Such stimulation could stimulate hypertrophic contribute drug-resistant hypertension patient populations loss-of-function

Язык: Английский

Necrosis drives susceptibility to Mycobacterium tuberculosis in Polg D257A mutator mice DOI Creative Commons
Cory J. Mabry, Chi G. Weindel, Lauren W. Stranahan

и другие.

Infection and Immunity, Год журнала: 2025, Номер unknown

Опубликована: Фев. 19, 2025

ABSTRACT The genetic and molecular determinants that underlie the heterogeneity of Mycobacterium tuberculosis (Mtb) infection outcomes in humans are poorly understood. Multiple lines evidence demonstrate mitochondrial dysfunction can exacerbate mycobacterial disease severity, mutations some genes confer susceptibility to humans. Here, we report mitochondria DNA (mtDNA) polymerase gamma potentiate Mtb mice. Polg D257A mutator mtDNA mice fail mount a protective innate immune response at an early time point, evidenced by high bacterial burdens, reduced M1 macrophages, excessive neutrophil infiltration lungs. Immunohistochemistry reveals signs enhanced necrosis lungs Mtb-infected mice, macrophages hypersusceptible extrinsic triggers necroptosis ex vivo . By assigning role for driving during infection, this work further highlights requirement homeostasis mounting balanced responses Mtb.

Язык: Английский

Процитировано

1
Loss-of-function mitochondrial DNA polymerase gamma variants cause vascular smooth muscle cells to secrete a diffusible mitogenic factor DOI Creative Commons

Samantha Rothwell,

Irvin Ng,

Sophia Shalchy-Tabrizi

и другие.

Frontiers in Physiology, Год журнала: 2025, Номер 15

Опубликована: Фев. 17, 2025

Introduction Mitochondrial dysfunction promotes vascular aging and disease through diverse mechanisms beyond metabolic supply, including calcium radical signaling inflammation. DNA (mtDNA) replication by the POLG-encoded mitochondrial polymerase (POLG) is critical for health. Loss-of-function POLG variants are associated with a predisposition to hypertension. We hypothesized that impaired POLG, reduced mtDNA copy number or other mechanisms, would promote smooth muscle hypertrophy hyperplasia drives remodeling Methods characterized effect of over-expressing were previously observed in cohort hypertensive patients (p.Tyr955Cys, p.Arg964Cys, p.Asn1098Ile, p.Arg1138Cys) A7r5 cells. Results AlphaFold modeling holoenzyme complexed predicted changes catalytic site p.Tyr955Cys p.Asn1098Ile variants, while p.Arg964Cys p.Arg1138Cys showed minimal effects. The number, assessed immunofluorescence droplet digital PCR, up 27% order > relative wild-type-transfected cultures. Loss was cultures grown low serum glucose media, but cell density increased same rank both 10% 1% serum. constructs contained Myc epitope, counterstaining which transfected cells untransfected neighbors. Live-cell imaging membrane potential TMRM oxygen species production MitoSOX little variants. had on consumption, Seahorse assay. growth analyses again decreased p.Arg1138Cys, HeLa Conditioned media from doubling times naïve Pharmacologically, wedelolactone MitoTEMPOL, not indomethacin PD98059, suppressed mitogenic effects Discussion conclude induces secretion signal even when below limit detection. Such stimulation could stimulate hypertrophic contribute drug-resistant hypertension patient populations loss-of-function

Язык: Английский

Процитировано

0