TY - JOUR
T1 - Mitofusin 2 (Mfn2) links mitochondrial and endoplasmic reticulum function with insulin signaling and is essential for normal glucose homeostasis
AU - Sebastián, David
AU - Hernández-Alvarez, María Isabel
AU - Segalés, Jessica
AU - Sorianello, Eleanora
AU - Muñoz, Juan Pablo
AU - Sala, David
AU - Waget, Aurélie
AU - Liesa, Marc
AU - Paz, José C.
AU - Gopalacharyulu, Peddinti
AU - Orešič, Matej
AU - Pich, Sara
AU - Burcelin, R.
AU - Palacín, Manuel
AU - Zorzano, Antonio
PY - 2012
Y1 - 2012
N2 - Mitochondria are dynamic organelles that play a key role in energy
conversion. Optimal mitochondrial function is ensured by a
quality-control system tightly coupled to fusion and fission. In this
connection, mitofusin 2 (Mfn2) participates in mitochondrial fusion and
undergoes repression in muscle from obese or type 2 diabetic patients.
Here, we provide in vivo evidence that Mfn2 plays an essential role in
metabolic homeostasis. Liver-specific ablation of Mfn2 in mice led to
numerous metabolic abnormalities, characterized by glucose intolerance
and enhanced hepatic gluconeogenesis. Mfn2 deficiency impaired insulin
signaling in liver and muscle. Furthermore, Mfn2 deficiency was
associated with endoplasmic reticulum stress, enhanced hydrogen peroxide
concentration, altered reactive oxygen species handling, and active
JNK. Chemical chaperones or the antioxidant N-acetylcysteine
ameliorated glucose tolerance and insulin signaling in liver-specific
Mfn2 KO mice. This study provides an important description of a unique
unexpected role of Mfn2 coordinating mitochondria and endoplasmic
reticulum function, leading to modulation of insulin signaling and
glucose homeostasis in vivo.
AB - Mitochondria are dynamic organelles that play a key role in energy
conversion. Optimal mitochondrial function is ensured by a
quality-control system tightly coupled to fusion and fission. In this
connection, mitofusin 2 (Mfn2) participates in mitochondrial fusion and
undergoes repression in muscle from obese or type 2 diabetic patients.
Here, we provide in vivo evidence that Mfn2 plays an essential role in
metabolic homeostasis. Liver-specific ablation of Mfn2 in mice led to
numerous metabolic abnormalities, characterized by glucose intolerance
and enhanced hepatic gluconeogenesis. Mfn2 deficiency impaired insulin
signaling in liver and muscle. Furthermore, Mfn2 deficiency was
associated with endoplasmic reticulum stress, enhanced hydrogen peroxide
concentration, altered reactive oxygen species handling, and active
JNK. Chemical chaperones or the antioxidant N-acetylcysteine
ameliorated glucose tolerance and insulin signaling in liver-specific
Mfn2 KO mice. This study provides an important description of a unique
unexpected role of Mfn2 coordinating mitochondria and endoplasmic
reticulum function, leading to modulation of insulin signaling and
glucose homeostasis in vivo.
KW - mitochondrial dynamics
KW - insulin resistance
KW - metabolism
KW - oxidative stress
U2 - 10.1073/pnas.1108220109
DO - 10.1073/pnas.1108220109
M3 - Article in a proceedings journal
SN - 0027-8424
VL - 109
SP - 5523
EP - 5528
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 14
ER -