bims-misrem 2021-09-05 papers

Elife. 2021 09 01. pii: e63453. [Epub ahead of print]10

The mitochondrial permeability transition pore activates the mitochondrial unfolded protein response and promotes aging.

Suzanne Angeli, Anna Foulger, Manish Chamoli, Tanuja Harshani Peiris, Akos Gerencser, Azar Asadi Shahmirzadi, Julie Andersen, Gordon Lithgow.

Mitochondrial activity determines aging rate and the onset of chronic diseases. The mitochondrial permeability transition pore (mPTP) is a pathological pore in the inner mitochondrial membrane thought to be composed of the F-ATP synthase (complex V). OSCP, a subunit of F-ATP synthase, helps protect against mPTP formation. How the destabilization of OSCP may contribute to aging, however, is unclear. We have found that loss OSCP in the nematode Caenorhabditis elegans initiates the mPTP and shortens lifespan specifically during adulthood, in part via initiation of the mitochondrial unfolded protein response (UPRmt). Pharmacological or genetic inhibition of the mPTP inhibits the UPRmt and restores normal lifespan. Loss of the putative pore-forming component of F-ATP synthase extends adult lifespan, suggesting that the mPTP normally promotes aging. Our findings reveal how an mPTP/UPRmt nexus may contribute to aging and age-related diseases and how inhibition of the UPRmt may be protective under certain conditions.

Keywords: C. elegans; F-ATP synthase; aging; c-subunit; cell biology; mitochondrial permeability transition pore; mitochondrial unfolded protein response; oscp/atp-3

DOI: https://doi.org/10.7554/eLife.63453

J Musculoskelet Neuronal Interact. 2021 Sep 01. 21(3): 387-396

Genetic variability affects the response of skeletal muscle to disuse.

Camilla Reina Maroni, Michael A Friedman, Yue Zhang, Michael J McClure, Stefania Fulle, Charles R Farber, Henry J Donahue.

OBJECTIVE: To examine whether genetic variability plays a role in skeletal muscle response to disuse.
METHODS: We examined skeletal muscle response to disuse in five different strains of mice: CAST/EiJ, NOD/ShiLtJ, NZO/HILtJ, 129S1/SvImJ and A/J. Mice had one limb immobilized by a cast for three weeks.
RESULTS: Response to immobilization was dependent on the strain of mice. Skeletal muscle mass/body weight was decreased by immobilization in all strains except 1291/SvImJ. Immobilization decreased absolute skeletal muscle mass in quadriceps and gastrocnemius in NOD/ShiltJ and NZO/HILtJ mice. Three weeks of immobilization resulted in an increase in quadriceps levels of atrogenes in CAST/EiJ. Immobilization resulted in an increase in quadriceps and gastrocnemius levels of Myh4 in CAST/EiJ. A similar trend was observed for Myh7 in gastrocnemius muscle. Immobilization resulted in a decrease of the p-p70S6K1/total p706SK1 ratio in quadriceps of NOD/ShiLtJ mice and the gastrocnemius of A/J mice. Immobilization did not affect the p-4EBP1/total 4EBP1 ratio in quadriceps of any of the strains examined. However, the p-4EBP1/total 4EBP1 ratio in gastrocnemius was greater in immobilized, relative to control, limbs in CAST/EiJ mice.
CONCLUSION: Genetic variability affects the response of skeletal muscle to disuse.

Keywords: Immobilization; Skeletal Muscle Atrophy

Elife. 2021 Aug 31. pii: e69312. [Epub ahead of print]10

The mechanism of MICU-dependent gating of the mitochondrial Ca2+ uniporter.

Vivek Garg, Junji Suzuki, Ishan Paranjpe, Tiffany Unsulangi, Liron Boyman, Lorin S Milescu, W Jonathan Lederer, Yuriy Kirichok.

Ca2+ entry into mitochondria is through the mitochondrial calcium uniporter complex (MCUcx), a Ca2+-selective channel composed of five subunit types. Two MCUcx subunits (MCU and EMRE) span the inner mitochondrial membrane, while three Ca2+-regulatory subunits (MICU1, MICU2 and MICU3) reside in the intermembrane space. Here we provide rigorous analysis of Ca2+ and Na+ fluxes via MCUcx in intact isolated mitochondria to understand the function of MICU subunits. We also perform direct patch clamp recordings of macroscopic and single MCUcx currents to gain further mechanistic insight. This comprehensive analysis shows that the MCUcx pore, composed of the EMRE and MCU subunits, is not occluded nor plugged by MICUs during the absence or presence of extramitochondrial Ca2+ as has been widely reported. Instead, MICUs potentiate activity of MCUcx as extramitochondrial Ca2+ is elevated. MICUs achieve this by modifying the gating properties of MCUcx allowing it to spend more time in the open state.

Keywords: molecular biophysics; mouse; structural biology

DOI: https://doi.org/10.7554/eLife.69312