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Review
. 2017 Aug;1858(8):602-614.
doi: 10.1016/j.bbabio.2017.01.004. Epub 2017 Jan 16.

Mitochondrial dysfunction and mitochondrial dynamics-The cancer connection

Satish Srinivasan  1 , Manti Guha  1 , Anna Kashina  1 , Narayan G Avadhani  2
Affiliations
Review

Mitochondrial dysfunction and mitochondrial dynamics-The cancer connection

Satish Srinivasan et al. Biochim Biophys Acta Bioenerg. 2017 Aug.

Abstract

Mitochondrial dysfunction is a hallmark of many diseases. The retrograde signaling initiated by dysfunctional mitochondria can bring about global changes in gene expression that alters cell morphology and function. Typically, this is attributed to disruption of important mitochondrial functions, such as ATP production, integration of metabolism, calcium homeostasis and regulation of apoptosis. Recent studies showed that in addition to these factors, mitochondrial dynamics might play an important role in stress signaling. Normal mitochondria are highly dynamic organelles whose size, shape and network are controlled by cell physiology. Defective mitochondrial dynamics play important roles in human diseases. Mitochondrial DNA defects and defective mitochondrial function have been reported in many cancers. Recent studies show that increased mitochondrial fission is a pro-tumorigenic phenotype. In this paper, we have explored the current understanding of the role of mitochondrial dynamics in pathologies. We present new data on mitochondrial dynamics and dysfunction to illustrate a causal link between mitochondrial DNA defects, excessive fission, mitochondrial retrograde signaling and cancer progression. This article is part of a Special Issue entitled Mitochondria in Cancer, edited by Giuseppe Gasparre, Rodrigue Rossignol and Pierre Sonveaux.

Keywords: Mitochondrial dysfunction; cancer; mitochondrial dynamics; mitochondrial fission; retrograde signaling.

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Conflict of interest statement

Conflict of Interest: The authors declare no conflict of interest.

Figures

Figure 1
Figure 1. Altered mitochondrial ultrastructure in response to mtDNA depletion
Electron micrographs of control, EtBr-treated mtDNA-depleted and Tfam shRNA-mtDNA depleted cells. Left panel: Scale Bar 2μm, magnification 10000x; Right panel: Scale Bar 100nm, magnification 75000x.
Figure 2
Figure 2. Altered mitochondrial fission and fusion dynamics in mtDNA depleted cells
(A) Immunofluorescence images showing OPA1 (mitochondrial fusion marker in red) and DAPI (nuclei in blue) staining pattern in control, mtDNA depleted (Tfam sh) and CcOIVi1kd C2C12 cells. (B) Primary esophageal epithelial cells derived from Tfam fl/fl mice expressing either Adeno GFP (control) or AdenoL2- Cre (Tfam KO) stained with OPA1 (mitochondrial fusion marker in red) and DAPI (nuclei in blue). (C) Primary esophageal epithelial cells derived from Tfam fl/fl mice expressing either Adeno GFP (control) or AdenoL2- Cre (Tfam KO) stained with DRP1 (mitochondrial fission marker in red) and DAPI (nuclei in blue). (D) Primary esophageal epithelial cells derived from Tfam fl/fl mice expressing either Adeno GFP (control) or AdenoL2- Cre (Tfam KO) treated with or without mDivi1 (10μM, 48h) stained with Texas-Red Phalloidin (red, actin) and DAPI (blue, nuclei). Images are captured under 40x objective of a NIKON E600 microscope.
Figure 3
Figure 3. Acquired Migratory pattern of C2C12 cells
(A) Windrose plot showing the directionality of migration of Control, mtDNA depleted and mtDNA depleted cells treated with mDivi1as indicated in the figure. Individual cells tracked are indicated by different colors. (B) Individual cells in each category were tracked using the Volocity software (Perkin Elmer) to estimate the maximum distance covered during the 10h migration. Movie Legends: Time lapse recordings for “scratch wound healing” migration assay: Control (Video1), mtDNA- depleted (Video 2) and mtDNA-depleted + mDivi1 treated (Video 3) C2C12 cells were grown to confluence and wounded with a pipette tip. Wound healing as a measure of cell motility and images were captured every 5 mins and followed for 10 hours.
Figure 4
Figure 4. Metabolic changes in response to mtDNA depletion
Intracellular lactate, fumarate and 2-hydroxyglutarate were quantified by reverse phase LC coupled to an Orbitrap Mass Spectrometer. Graphs show fold change in indicated metabolites between control and mtDNA depleted C2C12 cells. Values normalized to control cells.
Figure 5
Figure 5. MtDNA depletion induced cytoskeletal reorganization in immortalized cells
Control and mtDNA depleted C2C12 (A) and HEK293T (B) stained with Texas-Red® conjugated Phalloidin (Molecular Probes) for gamma Actin (red) and DAPI for nuclei (blue). Phalloidin staining was performed according to manufacturer s suggested protocol. Cells were imaged under Nikon E600 microscope 40x Objective. Scale Bar: 20μm.
Figure 6
Figure 6. Alterations in cellular morphology in Tfamfl/fl/Cre-primary esophageal cells
Real Time PCR quantitation of relative Tfam mRNA levels (A) and mtDNA content (B) in primary esophageal epithelial cells derived from Tfam fl/fl mice expressing either Adeno GFP (control) or AdenoL2- Cre (Tfam KO). (C) Cell Size distribution in primary esophageal epithelial cells derived from Tfam fl/fl mice expressing either Adeno GFP (control) or AdenoL2- Cre (Tfam KO) assessed on Nexcelom Vision CBA. (D) Primary esophageal epithelial cells derived from Tfam fl/fl mice expressing either Adeno GFP (control) or AdenoL2- Cre (Tfam KO) stained with Texas-Red Phalloidin (red, actin) and DAPI (blue, nuclei) imaged under 40x objective of a NIKON E600 microscope.
Figure 7
Figure 7. Three dimensional organoids in Tfamfl/fl/Cre-primary esophageal cells
Bright Field images of Hematoxylin-Eosin stained sections of 3D organoids from primary esophageal epithelial cells derived from Tfamfl/fl mice expressing either Adeno GFP (control) or AdenoL2-Cre (Tfam KO.
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