Borderline personality disorder (BPD) is a distressing condition with a symptomatology that includes increased sensitivity to social rejection, self-injury and subjective feeling of dysphoria. People classed with BPD often meet criteria for Major depressive disorder (MDD). BPD is still conceptualized in psychological terms as is its treatment. This article looks to define BPD on the basis of pathophysiological processes that overlap with those of depression by highlighting the role of astrocyte mitochondria dysregulation, particularly at sites of increased blood-brain barrier (BBB) permeability. The efficacy of ketamine as a fast-acting antidepressant in the treatment of MDD and BPD gives some indication as to the core changes pertinent to BPD and MDD pathophysiology. Although classically conceptualized as a post-synaptic N-methyl-d-aspartate receptor (NMDAr), antagonist, recent work shows ketamine to have direct effects on mitochondrial function. Being amphiphilic, ketamine can readily cross the BBB with astrocytes being the first CNS cell encountered. It is proposed that ketamine acts on the astrocyte mitochondrial inner membrane NMDAr. As ketamine has a short half-life, low dose ketamine has transient stress effects on mitochondrial function that leads to a preconditioning type effect by increasing mitochondrial resilience to subsequent challenges/stressors. This involves the upregulation of mitochondrial melatonin and humanin in astrocytes, which re-establish astrocyte function and also act extracellularly to dampen inflammation and oxidative stress in microglia, neurons and white matter oligodendrocytes. Pathophysiological changes in BPD (and MDD) are derived from suboptimal astrocyte mitochondrial function at sites of increased BBB permeability, including the medial prefrontal cortex (mPFC). When mPFC astrocyte metabolic function is restored, the mPFC re-establishes negative feedback on amygdala activity.