Mitochondrial lactate venting limits oxidative stress.

Area of Science:

• Cellular metabolism
• Mitochondrial function
• Neuroscience

Background:

• The "intracellular lactate shuttle" hypothesis suggests lactate fuels mitochondrial respiration.
• This hypothesis remains controversial, lacking direct evidence for lactate's role as a respiratory substrate.

Purpose of the Study:

• To investigate lactate's presence and function within the mitochondrial matrix.
• To determine if lactate directly energizes mitochondrial respiration.

Main Methods:

• Utilized genetically encoded lactate and redox sensors in cultured cells and in vivo neurons.
• Employed pharmacologic and genetic inhibition of the mitochondrial pyruvate carrier (MPC).

Main Results:

• Identified a dynamic lactate pool in the mitochondrial matrix influenced by extracellular and blood lactate levels.
• Observed lactate transport into mitochondria via a saturable pathway, partly dependent on MPC.
• Found that lactate does not measurably energize the electron transport chain.
• Demonstrated that energized mitochondria produce lactate from pyruvate, especially under hypoxia.
• Showed that MPC inhibition leads to matrix lactate and H₂O₂ accumulation, indicating a lactate-based "venting" mechanism.

Conclusions:

• Lactate enters mitochondria but does not directly fuel respiration under tested conditions.
• Mitochondria can produce lactate from pyruvate, modulated by energy status and hypoxia.
• Blocking MPC reveals a lactate-based mechanism that regulates matrix energy and reactive oxygen species production.