AMPK regulates Bcl2-L-13-mediated mitophagy induction for cardioprotection
Tomokazu Murakawa,
Jumpei Ito,
Mara-Camelia Rusu,
Manabu Taneike,
Shigemiki Omiya,
Javier Moncayo-Arlandi,
Chiaki Nakanishi,
Ryuta Sugihara,
Hiroki Nishida,
Kentaro Mine,
Roland Fleck,
Min Zhang,
Kazuhiko Nishida,
Ajay M. Shah,
Osamu Yamaguchi,
Yasushi Sakata,
Kinya Otsu
Affiliations
Tomokazu Murakawa
Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan; The School of Cardiovascular Medicine and Sciences, King’s College London British Heart Foundation Centre of Excellence, 125 Coldharbour Lane, SE5 9NU London, UK
Jumpei Ito
The School of Cardiovascular Medicine and Sciences, King’s College London British Heart Foundation Centre of Excellence, 125 Coldharbour Lane, SE5 9NU London, UK; National Cerebral and Cardiovascular Center, 6-1 Kishibe-Shimmachi, Suita, Osaka 564-8565, Japan
Mara-Camelia Rusu
The School of Cardiovascular Medicine and Sciences, King’s College London British Heart Foundation Centre of Excellence, 125 Coldharbour Lane, SE5 9NU London, UK
Manabu Taneike
Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan; The School of Cardiovascular Medicine and Sciences, King’s College London British Heart Foundation Centre of Excellence, 125 Coldharbour Lane, SE5 9NU London, UK
Shigemiki Omiya
The School of Cardiovascular Medicine and Sciences, King’s College London British Heart Foundation Centre of Excellence, 125 Coldharbour Lane, SE5 9NU London, UK; National Cerebral and Cardiovascular Center, 6-1 Kishibe-Shimmachi, Suita, Osaka 564-8565, Japan
Javier Moncayo-Arlandi
The School of Cardiovascular Medicine and Sciences, King’s College London British Heart Foundation Centre of Excellence, 125 Coldharbour Lane, SE5 9NU London, UK
Chiaki Nakanishi
The School of Cardiovascular Medicine and Sciences, King’s College London British Heart Foundation Centre of Excellence, 125 Coldharbour Lane, SE5 9NU London, UK; National Cerebral and Cardiovascular Center, 6-1 Kishibe-Shimmachi, Suita, Osaka 564-8565, Japan
Ryuta Sugihara
Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan
Hiroki Nishida
Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan
Kentaro Mine
Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan
Roland Fleck
Centre for Ultrastructural Imaging, New Hunts House, King’s College London, SE1 1UL London, UK; Randall Centre for Cell and Molecular Biophysics, King’s College London, SE1 1UL London, UK
Min Zhang
The School of Cardiovascular Medicine and Sciences, King’s College London British Heart Foundation Centre of Excellence, 125 Coldharbour Lane, SE5 9NU London, UK
Kazuhiko Nishida
The School of Cardiovascular Medicine and Sciences, King’s College London British Heart Foundation Centre of Excellence, 125 Coldharbour Lane, SE5 9NU London, UK
Ajay M. Shah
The School of Cardiovascular Medicine and Sciences, King’s College London British Heart Foundation Centre of Excellence, 125 Coldharbour Lane, SE5 9NU London, UK
Osamu Yamaguchi
National Cerebral and Cardiovascular Center, 6-1 Kishibe-Shimmachi, Suita, Osaka 564-8565, Japan; Department of Cardiology, Pulmonology, Hypertension & Nephrology, Ehime University Graduate School of Medicine, 454 Shitsukawa, Toon, Ehime 791-0295, Japan
Yasushi Sakata
Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan
Kinya Otsu
The School of Cardiovascular Medicine and Sciences, King’s College London British Heart Foundation Centre of Excellence, 125 Coldharbour Lane, SE5 9NU London, UK; National Cerebral and Cardiovascular Center, 6-1 Kishibe-Shimmachi, Suita, Osaka 564-8565, Japan; Corresponding author
Summary: The accumulation of damaged mitochondria in the heart is associated with heart failure. Mitophagy is an autophagic degradation system that specifically targets damaged mitochondria. We have reported previously that Bcl2-like protein 13 (Bcl2-L-13) mediates mitophagy and mitochondrial fission in mammalian cells. However, the in vivo function of Bcl2-L-13 remains unclear. Here, we demonstrate that Bcl2-L-13-deficient mice and knockin mice, in which the phosphorylation site (Ser272) on Bcl2-L-13 was changed to Ala, showed left ventricular dysfunction in response to pressure overload. Attenuation of mitochondrial fission and mitophagy led to impairment of ATP production in these mouse hearts. In addition, we identified AMPKα2 as the kinase responsible for the phosphorylation of Bcl2-L-13 at Ser272. These results indicate that Bcl2-L-13 and its phosphorylation play an important role in maintaining cardiac function. Furthermore, the amplitude of stress-stimulated mitophagic activity could be modulated by AMPKα2.
