Remodeling of mitochondrial morphology and function: an emerging hallmark of cellular reprogramming

Abstract

Research in the stem cell field has traditionally focused on understanding key transcriptional factors that provide pluripotent cell identity. However, much less is known about other critical non-transcriptional signaling networks that govern stem cell identity. Although we continue to gain critical insights into the mechanisms underlying mitochondrial morphology and function during cellular reprogramming - the process of reverting the fate of a differentiated cell into a stem cell, many uncertainties remain. Recent studies suggest an emerging landscape in which mitochondrial morphology and function have an active role in maintaining and regulating changes in cell identity. In this review, we will focus on these emerging concepts as crucial modulators of cellular reprogramming. Recognition of the widespread applicability of these concepts will increase our understanding of the mitochondrial mechanisms involved in cell identity, cell fate and disease.

Keywords: BCL-2 family; apoptosis; mitochondria; mitochondrial dynamics.

Figure 1. FIGURE 1: Emerging mitochondria-related hallmarks of reprogramming.

Left side: Differentiated cells (such as fibroblasts) have an elongated mitochondrial network with a preference for oxidative phosphorylation (OXPHOS) as a source of energy and are relatively resistant to apoptosis stimuli. Right side: After reprogramming, cells now have a fragmented mitochondrial network with a switch to using glycolysis as a preferred bioenergetic source. Cells become increasingly sensitive to cell death due to at least two main mechanisms: increased mitochondrial priming and pre-activated BAX.

Figure 2. FIGURE 2: Scheme of the mitochondrial pathway of apoptosis.

Stress-induced activation of BAX/BAK leading to mitochondrial outer membrane permeabilization and cytochrome c release to the cytosol. Anti-apoptotic proteins block BAK/BAX activation/oligomerization induced by BH3-only proteins. BCL-XL: B-cell lymphoma extra-large; MCL-1: myeloid cell leukemia 1; BID: BH3-interacting domain death agonist; BIM: BCL-2 interacting mediator of cell death; PUMA: P53-upregulated modulator of apoptosis.

Figure 3. FIGURE 3: BAX activation in stem cells.

Besides high mitochondrial priming, human ESCs also have an active form of BAX at the Golgi that rapidly translocates to the mitochondria under apoptosis stimuli. Active form of BAX: BAX 6A7; Golgi apparatus marker: TGN46.

Figure 4. FIGURE 4: Mitochondrial dynamics.

Mitochondrial fusion and fission are regulated by guanosine triphosphatases (GTPases) proteins: DRP1 mediates fission, OPA1 and Mitofusins (not shown) regulate mitochondrial fusion. In stem cells, the anti-apoptotic protein MCL1 has been shown to interact with DRP1 at the outer mitochondrial membrane and with OPA1 at the matrix.