NCLX: the mitochondrial sodium calcium exchanger

Area of Science:

• Mitochondrial physiology
• Cellular calcium homeostasis
• Molecular biology

Background:

• Mitochondrial matrix free Ca(2+) concentration ([Ca(2+)]m) governs ATP production and other vital processes.
• Mitochondrial Ca(2+) levels are determined by the balance of influx via the mitochondrial Ca(2+) uniporter (MCU) and efflux pathways.
• A Na(+)/Ca(2+) exchanger has long been suspected as the major mitochondrial Ca(2+) efflux route in mammalian tissues.

Purpose of the Study:

• To review and analyze experimental evidence for the mitochondrial Na(+)/Ca(2+) exchanger.
• To discuss the role of the newly identified NCLX protein (FLJ22233 gene product) in mitochondrial Ca(2+) efflux.
• To explore the quantitative and qualitative aspects of NCLX function and its physiological implications.

Main Methods:

• Literature review and analysis of experimental evidence spanning 40 years.
• Discussion of the molecular identity and function of the NCLX protein.
• Examination of NCLX's unique properties, including Li(+)/Ca(2+) exchange.

Main Results:

• Strong evidence supports a Na(+)/Ca(2+) exchanger as the primary pathway for mitochondrial Ca(2+) efflux.
• The human FLJ22233 gene product, named NCLX, mediates Na(+)/Ca(2+) and Li(+)/Ca(2+) exchange across the inner mitochondrial membrane.
• NCLX offers new molecular tools to investigate unresolved quantitative aspects of mitochondrial Ca(2+) efflux.

Conclusions:

• The discovery of NCLX provides the molecular identity of the mitochondrial Na(+)/Ca(2+) exchanger.
• NCLX's properties, including stoichiometry and electrogenicity, require further investigation.
• Understanding NCLX function is critical for elucidating mitochondrial Ca(2+) dynamics and its physiological roles in systole and diastole.