Most axonal mitochondria in cortical pyramidal neurons lack mitochondrial DNA and consume ATP

Abstract

In neurons of the mammalian central nervous system (CNS), axonal mitochondria are thought to be indispensable for supplying ATP during energy-consuming processes such as neurotransmitter release. Here, we demonstrate using multiple, independent, in vitro and in vivo approaches that the majority (~80-90%) of axonal mitochondria in cortical pyramidal neurons (CPNs), lack mitochondrial DNA (mtDNA). Using dynamic, optical imaging analysis of genetically encoded sensors for mitochondrial matrix ATP and pH, we demonstrate that in axons of CPNs, but not in their dendrites, mitochondrial complex V (ATP synthase) functions in a reverse way, consuming ATP and protruding H+ out of the matrix to maintain mitochondrial membrane potential. Our results demonstrate that in mammalian CPNs, axonal mitochondria do not play a major role in ATP supply, despite playing other functions critical to regulating neurotransmission such as Ca2+ buffering.

Compartmental Differences in the Retinal Ganglion Cell Mitochondrial Proteome

“…While the relative abundances of these proteins and the relative activity levels of the electron transport chain in the two compartments remain to be validated, it would seem surprising for axonal mitochondria to have a lower ATP-generating capacity than their counterparts in the RGC soma and dendrites. However, recent work in cortical projection neurons has cast doubt on the role of oxidative phosphorylation in providing for the energy needs of axons, potentially indicating that mitochondrial functions other than ATP generation may be of particular importance in neuronal axons 80 .…”

Mitochondria inside acute myeloid leukemia cells hydrolyze ATP to resist chemotherapy

“…In respiratory incompetent cells, polarization can also be sustained via cytosol to matrix ATP transport and/or ATP hydrolysis by the reversible ATP synthase reaction [27][28][29][30][31] . Thus, in the absence of a sufficient proton-motive force, ATP synthase reverts to an F1-ATPase, converting the free energy available in the cell's phosphate potential to a polarized mitochondrial inner membrane [27][28][29][30][31] . Maintenance of ΔΨm via matrix F1-ATPase activity has been demonstrated to be critical for cell survival in the context of respiratory complex lesions 27,32 .…”

“…Mitochondrial polarization is canonically generated via the proton pumping respiratory complexes (i.e., complexes I/III/IV). In respiratory incompetent cells, polarization can also be sustained via cytosol to matrix ATP transport and/or ATP hydrolysis by the reversible ATP synthase reaction [27][28][29][30][31] . Thus, in the absence of a sufficient proton-motive force, ATP synthase reverts to an F1-ATPase, converting the free energy available in the cell's phosphate potential to a polarized mitochondrial inner membrane [27][28][29][30][31] .…”