TCA Cycle and Mitochondrial Membrane Potential Are Necessary for Diverse Biological Functions

Abstract

Mitochondrial metabolism is necessary for the maintenance of oxidative TCA cycle function and mitochondrial membrane potential. Previous attempts to decipher whether mitochondria are necessary for biological outcomes have been hampered by genetic and pharmacologic methods that simultaneously disrupt multiple functions linked to mitochondrial metabolism. Here, we report that inducible depletion of mitochondrial DNA (ρ° cells) diminished respiration, oxidative TCA cycle function and the mitochondrial membrane potential resulting in diminished cell proliferation, hypoxic activation of HIF-1, and specific histone acetylation marks. Genetic reconstitution only of the oxidative TCA cycle function specifically in these inducible ρ° cells restored metabolites resulting in reestablishment of histone acetylation. In contrast, genetic reconstitution of the mitochondrial membrane potential restored ROS, which were necessary for hypoxic activation of HIF-1 and cell proliferation. These results indicate that distinct mitochondrial functions associated with respiration are necessary for cell proliferation, epigenetics, and HIF-1 activation.

Iron Deprivation Induces Transcriptional Regulation of Mitochondrial Biogenesis

“…Therefore, the observed changes in methylation and acetylation could, for example, be due to iron deprivation-induced reductions in these cofactors and a subsequent reduction in the activity of the iron-O 2 -␣-ketoglutarate-dependent lysine demethylases or acetyl-CoA-dependent lysine acetyltransferases. In line with this, a reduction in histone acetylation was recently observed in cells depleted of mitochondrial DNA, and genetic restoration of the oxidative tricarboxylic acid cycle and its metabolites reversed this effect (61). Additionally, as part of the mitochondrial unfolded protein response (UPR mt ), increased expression of the HDAC SIRT7 and its interaction with the transcription factor NRF1, a key regulator of mitochondrial biogenesis, led to the transcriptional repression of nuclear genes encoding mitochondrial proteins (62).…”

Metabolic Plasticity as a Determinant of Tumor Growth and Metastasis

“…On the basis of the observation that breast cancer cells produce 80% of their ATP via mitochondrial-dependent metabolism, the concept of "oxidative tumors" has been introduced to describe ATP production by OXPHOS from glucose, fatty acids, or glutamine oxidation (13)(14)(15). In addition, maintenance of mitochondrial membrane potential by the electron transport chain is required to support the proliferation of cancer cells (16). Tumor cells can also adopt intermediate metabolic phenotypes.…”

Metformin targets histone acetylation in cancer-prone epithelial cells

“…18 Although the latter scenario appears counterintuitive, it should be noted that pyruvate kinase (PK), especially the isoenzyme PKM2, and mitochondrial PDC are translocated and form a complex in the nucleus with a histone acetyl transferase to locally produce acetyl-CoA and drive specific acetylation of histone marks. 57,58 Moreover, nuclear PKM2 operates not only as a biosynthetic enzyme to produce pyruvate to be used by PDC for nuclear generation of acetyl-CoA, but also as a non-canonical kinase that binds and phosphorylates histone H3 at T11 to promote subsequent acetylation of H3 at K9. 59 Because metformin can reduce not only pyruvate dehydrogenase activity but also impairs nuclear PKM2 function, [60][61][62] it might be argued that the ability of metformin to target the metabolism-epigenome axis involves the direct effects of ACPEs on histone acetylation/phosphorylation.…”