OPA1‐dependent cristae modulation is essential for cellular adaptation to metabolic demand

Abstract

Cristae, the organized invaginations of the mitochondrial inner membrane, respond structurally to the energetic demands of the cell. The mechanism by which these dynamic changes are regulated and the consequences thereof are largely unknown. Optic atrophy 1 (OPA1) is the mitochondrial GTPase responsible for inner membrane fusion and maintenance of cristae structure. Here, we report that OPA1 responds dynamically to changes in energetic conditions to regulate cristae structure. This cristae regulation is independent of OPA1's role in mitochondrial fusion, since an OPA1 mutant that can still oligomerize but has no fusion activity was able to maintain cristae structure. Importantly, OPA1 was required for resistance to starvation-induced cell death, for mitochondrial respiration, for growth in galactose media and for maintenance of ATP synthase assembly, independently of its fusion activity. We identified mitochondrial solute carriers (SLC25A) as OPA1 interactors and show that their pharmacological and genetic blockade inhibited OPA1 oligomerization and function. Thus, we propose a novel way in which OPA1 senses energy substrate availability, which modulates its function in the regulation of mitochondrial architecture in a SLC25A protein-dependent manner.

StarD7 Protein Deficiency Adversely Affects the Phosphatidylcholine Composition, Respiratory Activity, and Cristae Structure of Mitochondria

“…These results indicate that StarD7 is important for mitochondrial ATP generation and cell growth. These phenotypes of StarD7-KO cells were similar to the cells having optic atrophy 1 (Opa1) deficiency, which is an important protein for the maintenance of cristae architecture (13).…”

“…Analysis of Opa1 Oligomerization-Opa1 oligomerization was analyzed as described before (13). Briefly, after washing with PBS, cells were treated with 1 mM bismaleimidohexane (Thermo Fisher Scientific), a cell-permeable cross-linker, for 20 min at 37°C.…”

“…The inner membrane dynamin-like GTPase Opa1 mediates inner membrane mitochondrial fusion and morphology (13,15,16). Inner membrane proteases such as Oma1 cleave long membrane-bound Opa1 forms (Opa1-L) into short soluble forms (Opa1-S).…”

Loss of Mitochondrial Function Impairs Lysosomes

“…1G, Hoechst), and AKO animals had normal numbers of neurons in layer V (28). Similar SOD1-negative vacuoles were observed in MEFs lacking the mitochondrial inner membrane GTPase OPA1, 4 a protein required for mitochondrial fusion, and to maintain cristae structure (31,37,38). Together, these results indicate that inhibition of mitochondrial function causes the occurrence of large intracytoplasmic vacuoles.…”

The mitochondrial dynamics in cancer and immune-surveillance

“…Downregulation of Mfns or Opa-1 levels reduces OXPHOS and ATP production in several cell models [81][82][83]. In line with this, Opa-1-driven cristae remodelling is strictly required for regulating ATP production upon different cell needs [84], while Mfn-2 overexpression in myotubes can upregulate the transcription of OXPHOS genes [85]. However, in HeLa cells, prolonged Drp1 downregulation can reduce respiration levels [86], this suggesting that optimal OXPHOS activity requires a balanced equilibrium in mitochondrial morphology.…”