Figure 1. Safeguard mechanisms preventing extreme mitochondrial fusion to maintain respiratory function.

In healthy cells (A), both fission and fusion events are dynamically balanced and mitochondria display an intermediate network distribution, which sustain an optimal respiratory capacity. Inhibition of the fission machinery, by the genetic deletion of Drp1 or its receptor MFF, induces the formation of a hyperfused mitochondrial network (B). Elongated mitochondria in Drp1‐KO cells exhibit localized, repetitive, and transient loss of membrane potential, a phenomenon named flickering, that activate OMA1, which promote OPA1 cleavage, S‐OPA1 accumulation, and, subsequently, the inhibition of excessive mitochondrial fusion. In addition, Drp1‐deficient cells exhibit lower levels of Mfn1, as a second protective mechanism to prevent further and deleterious mitochondrial fusion and thus to maintain the mitochondrial bioenergetic status. Inhibition of OMA1 activity and re‐expression of Mfn1 in Drp1‐KO cells lead to extreme mitochondrial fusion and the complete loss of membrane potential (C), which are correlated to the decrease of mitochondrial bioenergetics. OMM: Outer mitochondrial membrane; IMM: Inner mitochondrial membrane; IMS: Intermembrane space; KO: Knock‐out; WT: Wild‐type; KD: Knockdown; OE: Overexpression.