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preclinical MM cell and animals models, which will be discussed below.

DISRUPTION OF MITOCHONDRIAL DYNAMICS IN MALIGNANT MESOTHELIOMA
The mitochondria are thought of as a dynamic network that fuse (fusion) and divide (fission) in order to
adapt to the metabolic needs of the cell . The process of fission is mediated by the GTPases dynamin-
[62]
[63]
related protein1 (Drp1) and dynamin 2 (Dnm2) . Similarly, mitochondrial fusion is mediated by
[64]
mitofusins Mfn1 and Mfn2 that help perform the fusion of two mitochondrial membranes . In cancerous
cells, the mitochondrial network is often fragmented, and redox-dependent signaling is believed to be key to
these shape changes [65,66] . One of these pathways is hypoxia-induced mitochondrial fission, which occurs
when HIFs induce Drp1 expression. In addition to mitochondrial fragmentation, HIF expression is linked
to increased metastatic activity. This suggests that HIFs are an important mediator for both mitochondrial
fission and cancer cell proliferation [67,68] . Another important mediator is the p38 mitogen-activated protein
[69]
kinase (MAPK), which stimulates stress response pathways upon receiving redox signals . One direct way
is to phosphorylate Drp1 directly to induce mitochondrial fission .
[70]
The transcription factor nuclear factor κB (NF-κB), which plays a role in inflammation and is upregulated in
cancer, is also thought to alter mitochondrial dynamics. Elevated NF-κB levels in cigarette smoke-induced
mitochondrial fragmentation were found to correlate with increased expression of Drp1 and decreased
expression of Mfn2 . More recent research has also shown that the principal component of that pathway is
[71]
the NF-κB inducing kinase (NIK). In addition to having pro-fission activity, NIK was also shown to
promote mitochondrial migration towards the cell periphery, which was shown to correlate with increased
tumor invasiveness [72,73] . NF-κB activity is upregulated following asbestos exposure , and sustained NF-κB
[74]
[75]
activity has been observed in MM cells . Downregulation of NF-κB with Onconase decreased MM
proliferation and invasion . Although mitochondrial defects were not reported in these studies, the cellular
[76]
responses observed warrant evaluating strategies targeting NF-κB with disruption of mitochondrial
dynamics.

MM cells also appear to demonstrate a difference in mitochondrial morphologies. A study performed by
Lennon et al. evaluated the fission/fusion rate of various MM cells using fractal dimension and lacunarity
measurements to characterize mitochondrial architectures . They found that MM cell lines displayed a low
[77]
fractal dimension and high lacunarity compared to control mesothelial cells. The low fractal dimension and
high lacunarity both indicate a high rate of mitochondrial fission . DRP1 is upregulated in many cancer
[77]
types and supports tumor growth and metastasis . Mitochondrial dynamics, including fission, appear to be
[78]
linked to cell cycle at the G2/M phase, as it is an important checkpoint to ensure an even distribution of
mitochondria. Drp1, therefore, plays an important role in mediating cell cycle progression . Interestingly,
[79]
we found that PRX3 expression in MM cells mediates Drp1 expression and provides evidence that this
affects mitochondrial dynamics through activation of Drp1. This was demonstrated in an experiment where
cells failed to progress through the G2/M phase when PRX3 expression was inhibited and DRP1
phosphorylation at a key regulatory serine was coincidingly reduced . Disabling the receptor tyrosine
[23]
kinase MET with MGCD516 in MM cells led to a loss of DRP1 activity that accompanied reduced viability,
[80]
migration, and invasion . Combining MGCD516 with the proposed mitochondrial fission inhibitor Mdivi-
[80]
1 induced cell death to a greater extent than either drug used alone . Given that DRP1 expression is
[77]
upregulated in MM , the unique mitochondrial morphologies of MM cells and the connection between
[81]
mitochondrial redox status, DRP1 activity and cell cycle progression targeting mitochondrial morphology
[23]
in MM may be a viable therapeutic approach. Lennon et al. (2016) also studied the effects of mitochondrial
inhibitors metformin and Mdivi-1 . Metformin, which inhibits complex I of the electron transport chain,
[77]
appeared to be highly effective against MM cell lines with a low fractal dimension and a high lacunarity.