The Upsides and Downsides of Organelle Interconnectivity

Abstract

Interconnectivity and feedback control are hallmarks of biological systems. This includes communication between organelles, which allows them to function and adapt to changing cellular environments. While the specific mechanisms for all communications remain opaque, unraveling the wiring of organelle networks is critical to understand how biological systems are built and why they might collapse, as occurs in aging. A comprehensive understanding of all the routes involved in inter-organelle communication is still lacking, but important themes are beginning to emerge, primarily in budding yeast. These routes are reviewed here in the context of sub-system proteostasis and complex adaptive systems theory.

Keywords: aging; inter-organelle communication; protein quality control; yeast.

Figure 1. Examples of interconnections and compensatory responses of subsystem PQCs

In all figures, a, b, are different types of organelles, “c” is the cytoplasm, and “d” the nucleus. (A) Interconnection by shared PQC factors. State 1: A shared PQC factor (red circles) is utilized for quality control in several subsystems, a,b, and c. Perturbation: A transition from the normal state (state 1) to a chronic malfunctioning of one subsystem (a) during generates internal damage (orange thread) that requires a higher load of the shared PQC factor (red circles) to assuage. As a consequence, the PQC factor becomes limited at other subsystems (b & c) leading to elevated damage also in these systems. Response: The accumulated damage trigger a response (hatched arrow) in “d” to produce more of the PQC factor that can compensate for the titration of the shared factor by the chronically malfunction subsystem “a”. State 2: The new state (compensatory state) is different from the original state but might be compatible with function and survival in the face of a chronic functional decline of subsystem “a”. (B) Interconnection and compensation by trafficking. State 1: The accumulation of a damaged and potentially toxic form of a molecule (orange thread) in subsystem “c” is in this example dealt with by a temporal PQC (purple diamond) destroying, or clearing, the damage and a spatial PQC (green and red circles) detoxifying the damaged molecule by spatial sequestration during a normal state. The latter PQC makes use of trafficking between subsystems “b” and “a” as detailed in the text. Perturbation: If the function of the temporal PQC in “c” is irreversibly diminished (crossed-over purple diamond), accumulation of damaged and toxic molecules increase. Response: A feedback signaling (hatched arrow) response can elevate the titer of a limiting spatial PQC factor (green circles) that boost the trafficking between “b” and “a” allowing the detoxification of damaged molecules. State2: The cell has reached a new functional state that compensate for the irreversible decline in temporal PQC. (C) Interconnection by protons, metabolites and small molecules. State 1: The concentration of a small metabolite (blueness of subsystem indicate concentration of the metabolite) is regulated such that every subsystem displays a concentration compatible with function and damage control. Perturbation: In this example, subsystem “a” fails to retain the metabolite, which leaks into subsystem “c”, and later subsystem “b”. The change in the milieu of these subsystems is promoting damage (orange threads). Response: The accumulation of damage (and perhaps the concentration of the metabolite itself) triggers a response (hatched arrows) aimed at producing PQC factors (purple diamonds and green circles) that remove such damage from both subsystems. State 2: A new state is reached compensating for, but not fixing, the chronic failure of subsystem “a”.

Figure 2. How inter-organelle interactions can mediate a cascade of decline that define a cellular aging process

A schematic representation of the changes that occur during replicative aging of S. cerevisiae cells within, and between, the plasma membrane, vacuole, mitochondria and nucleus is presented in a series of five panels. Cellular age increase from top to bottom. (A) Interactions in newborn mother cells. Representation of a newborn cell in which cytoplasmic protons (H⁺) are being pumped into the vacuole and across the plasma membrane (by the V-ATPase and Pma1, respectively). Consequently the vacuole is relatively acidic (represented by large “H⁺” and bright green vacuole color) and is able to store amino acids because of the activity of the antiporters (brown disc with dual arrows) that use the acidity of the vacuole to bring in amino acids. On the right side of the figure, mitochondria are shown providing the obligate cofactors, iron-sulfur clusters, to DNA repair and replication enzymes in the nucleus. (B) Elevated Pma1 competes with V-ATPase for cytoplasmic protons. In this first step of the aging cascade, increased levels of Pma1 (3x more Pma1 trapezoids) pump more protons from the cytoplasm to the plasma membrane at the expense of the vacuole (smaller “H⁺” and less bright green) (C) Reduced vacuole acidity leads to mitochondrial dysfunction. The amino acid antiporters require an acidic vacuole; amino acids are no longer imported into the vacuole and consequently buildup in the cytoplasm. The increased level of cytoplasmic amino acids leads to mitochondrial dysfunction (reduced ΔΨ; indicated by faded mitochondrial color). (D) Reduced iron-sulfur cluster production follows mitochondrial dysfunction. Fewer iron-sulfur clusters make there way to the nucleus (dotted line). (E) Genome instability increases with reduced DNA enzyme activities. Iron-sulfur cluster requiring DNA repair and replication enzymes are proposed to have reduced activity (orange to red) because of fewer available iron-sulfur clusters. Aberrant chromosomes are represented by dashed lines.

Figure 2. How inter-organelle interactions can mediate a cascade of decline that define a cellular aging process

A schematic representation of the changes that occur during replicative aging of S. cerevisiae cells within, and between, the plasma membrane, vacuole, mitochondria and nucleus is presented in a series of five panels. Cellular age increase from top to bottom. (A) Interactions in newborn mother cells. Representation of a newborn cell in which cytoplasmic protons (H⁺) are being pumped into the vacuole and across the plasma membrane (by the V-ATPase and Pma1, respectively). Consequently the vacuole is relatively acidic (represented by large “H⁺” and bright green vacuole color) and is able to store amino acids because of the activity of the antiporters (brown disc with dual arrows) that use the acidity of the vacuole to bring in amino acids. On the right side of the figure, mitochondria are shown providing the obligate cofactors, iron-sulfur clusters, to DNA repair and replication enzymes in the nucleus. (B) Elevated Pma1 competes with V-ATPase for cytoplasmic protons. In this first step of the aging cascade, increased levels of Pma1 (3x more Pma1 trapezoids) pump more protons from the cytoplasm to the plasma membrane at the expense of the vacuole (smaller “H⁺” and less bright green) (C) Reduced vacuole acidity leads to mitochondrial dysfunction. The amino acid antiporters require an acidic vacuole; amino acids are no longer imported into the vacuole and consequently buildup in the cytoplasm. The increased level of cytoplasmic amino acids leads to mitochondrial dysfunction (reduced ΔΨ; indicated by faded mitochondrial color). (D) Reduced iron-sulfur cluster production follows mitochondrial dysfunction. Fewer iron-sulfur clusters make there way to the nucleus (dotted line). (E) Genome instability increases with reduced DNA enzyme activities. Iron-sulfur cluster requiring DNA repair and replication enzymes are proposed to have reduced activity (orange to red) because of fewer available iron-sulfur clusters. Aberrant chromosomes are represented by dashed lines.

Figure 2. How inter-organelle interactions can mediate a cascade of decline that define a cellular aging process

A schematic representation of the changes that occur during replicative aging of S. cerevisiae cells within, and between, the plasma membrane, vacuole, mitochondria and nucleus is presented in a series of five panels. Cellular age increase from top to bottom. (A) Interactions in newborn mother cells. Representation of a newborn cell in which cytoplasmic protons (H⁺) are being pumped into the vacuole and across the plasma membrane (by the V-ATPase and Pma1, respectively). Consequently the vacuole is relatively acidic (represented by large “H⁺” and bright green vacuole color) and is able to store amino acids because of the activity of the antiporters (brown disc with dual arrows) that use the acidity of the vacuole to bring in amino acids. On the right side of the figure, mitochondria are shown providing the obligate cofactors, iron-sulfur clusters, to DNA repair and replication enzymes in the nucleus. (B) Elevated Pma1 competes with V-ATPase for cytoplasmic protons. In this first step of the aging cascade, increased levels of Pma1 (3x more Pma1 trapezoids) pump more protons from the cytoplasm to the plasma membrane at the expense of the vacuole (smaller “H⁺” and less bright green) (C) Reduced vacuole acidity leads to mitochondrial dysfunction. The amino acid antiporters require an acidic vacuole; amino acids are no longer imported into the vacuole and consequently buildup in the cytoplasm. The increased level of cytoplasmic amino acids leads to mitochondrial dysfunction (reduced ΔΨ; indicated by faded mitochondrial color). (D) Reduced iron-sulfur cluster production follows mitochondrial dysfunction. Fewer iron-sulfur clusters make there way to the nucleus (dotted line). (E) Genome instability increases with reduced DNA enzyme activities. Iron-sulfur cluster requiring DNA repair and replication enzymes are proposed to have reduced activity (orange to red) because of fewer available iron-sulfur clusters. Aberrant chromosomes are represented by dashed lines.

Figure 2. How inter-organelle interactions can mediate a cascade of decline that define a cellular aging process

A schematic representation of the changes that occur during replicative aging of S. cerevisiae cells within, and between, the plasma membrane, vacuole, mitochondria and nucleus is presented in a series of five panels. Cellular age increase from top to bottom. (A) Interactions in newborn mother cells. Representation of a newborn cell in which cytoplasmic protons (H⁺) are being pumped into the vacuole and across the plasma membrane (by the V-ATPase and Pma1, respectively). Consequently the vacuole is relatively acidic (represented by large “H⁺” and bright green vacuole color) and is able to store amino acids because of the activity of the antiporters (brown disc with dual arrows) that use the acidity of the vacuole to bring in amino acids. On the right side of the figure, mitochondria are shown providing the obligate cofactors, iron-sulfur clusters, to DNA repair and replication enzymes in the nucleus. (B) Elevated Pma1 competes with V-ATPase for cytoplasmic protons. In this first step of the aging cascade, increased levels of Pma1 (3x more Pma1 trapezoids) pump more protons from the cytoplasm to the plasma membrane at the expense of the vacuole (smaller “H⁺” and less bright green) (C) Reduced vacuole acidity leads to mitochondrial dysfunction. The amino acid antiporters require an acidic vacuole; amino acids are no longer imported into the vacuole and consequently buildup in the cytoplasm. The increased level of cytoplasmic amino acids leads to mitochondrial dysfunction (reduced ΔΨ; indicated by faded mitochondrial color). (D) Reduced iron-sulfur cluster production follows mitochondrial dysfunction. Fewer iron-sulfur clusters make there way to the nucleus (dotted line). (E) Genome instability increases with reduced DNA enzyme activities. Iron-sulfur cluster requiring DNA repair and replication enzymes are proposed to have reduced activity (orange to red) because of fewer available iron-sulfur clusters. Aberrant chromosomes are represented by dashed lines.

Figure 2. How inter-organelle interactions can mediate a cascade of decline that define a cellular aging process

A schematic representation of the changes that occur during replicative aging of S. cerevisiae cells within, and between, the plasma membrane, vacuole, mitochondria and nucleus is presented in a series of five panels. Cellular age increase from top to bottom. (A) Interactions in newborn mother cells. Representation of a newborn cell in which cytoplasmic protons (H⁺) are being pumped into the vacuole and across the plasma membrane (by the V-ATPase and Pma1, respectively). Consequently the vacuole is relatively acidic (represented by large “H⁺” and bright green vacuole color) and is able to store amino acids because of the activity of the antiporters (brown disc with dual arrows) that use the acidity of the vacuole to bring in amino acids. On the right side of the figure, mitochondria are shown providing the obligate cofactors, iron-sulfur clusters, to DNA repair and replication enzymes in the nucleus. (B) Elevated Pma1 competes with V-ATPase for cytoplasmic protons. In this first step of the aging cascade, increased levels of Pma1 (3x more Pma1 trapezoids) pump more protons from the cytoplasm to the plasma membrane at the expense of the vacuole (smaller “H⁺” and less bright green) (C) Reduced vacuole acidity leads to mitochondrial dysfunction. The amino acid antiporters require an acidic vacuole; amino acids are no longer imported into the vacuole and consequently buildup in the cytoplasm. The increased level of cytoplasmic amino acids leads to mitochondrial dysfunction (reduced ΔΨ; indicated by faded mitochondrial color). (D) Reduced iron-sulfur cluster production follows mitochondrial dysfunction. Fewer iron-sulfur clusters make there way to the nucleus (dotted line). (E) Genome instability increases with reduced DNA enzyme activities. Iron-sulfur cluster requiring DNA repair and replication enzymes are proposed to have reduced activity (orange to red) because of fewer available iron-sulfur clusters. Aberrant chromosomes are represented by dashed lines.

Figure 2. How inter-organelle interactions can mediate a cascade of decline that define a cellular aging process

A schematic representation of the changes that occur during replicative aging of S. cerevisiae cells within, and between, the plasma membrane, vacuole, mitochondria and nucleus is presented in a series of five panels. Cellular age increase from top to bottom. (A) Interactions in newborn mother cells. Representation of a newborn cell in which cytoplasmic protons (H⁺) are being pumped into the vacuole and across the plasma membrane (by the V-ATPase and Pma1, respectively). Consequently the vacuole is relatively acidic (represented by large “H⁺” and bright green vacuole color) and is able to store amino acids because of the activity of the antiporters (brown disc with dual arrows) that use the acidity of the vacuole to bring in amino acids. On the right side of the figure, mitochondria are shown providing the obligate cofactors, iron-sulfur clusters, to DNA repair and replication enzymes in the nucleus. (B) Elevated Pma1 competes with V-ATPase for cytoplasmic protons. In this first step of the aging cascade, increased levels of Pma1 (3x more Pma1 trapezoids) pump more protons from the cytoplasm to the plasma membrane at the expense of the vacuole (smaller “H⁺” and less bright green) (C) Reduced vacuole acidity leads to mitochondrial dysfunction. The amino acid antiporters require an acidic vacuole; amino acids are no longer imported into the vacuole and consequently buildup in the cytoplasm. The increased level of cytoplasmic amino acids leads to mitochondrial dysfunction (reduced ΔΨ; indicated by faded mitochondrial color). (D) Reduced iron-sulfur cluster production follows mitochondrial dysfunction. Fewer iron-sulfur clusters make there way to the nucleus (dotted line). (E) Genome instability increases with reduced DNA enzyme activities. Iron-sulfur cluster requiring DNA repair and replication enzymes are proposed to have reduced activity (orange to red) because of fewer available iron-sulfur clusters. Aberrant chromosomes are represented by dashed lines.